CN117242172A - 用于产生能够直接诱导原始生殖细胞的形成性多能干细胞的方法 - Google Patents
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Abstract
本公开内容的方面涉及通过在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF‑β)激活剂和WNT激活剂的培养基中培养细胞来产生形成性多能干细胞(PSC)的方法。还提供了用于产生形成性多能干细胞的体外培养系统。
Description
相关申请的交叉引用
本申请要求2020年10月19日提交的临时申请号63/093,680的优先权,其全部内容通过引用并入本文。
序列表
本申请包含序列表,该序列表已通过EFS-Web以ASCII格式提交,并通过引用整体并入本文。ASCII副本名为106546-703050_PCT-Sequence-Listing_ST25.txt,大小为47KB。
领域
本公开内容提供包含形成性多能干细胞(PSC)的组合物和用于产生形成性多能干细胞(PSC)的方法,以及包含此类的体外培养系统。
背景
多能性(单个细胞产生成体生物体的所有谱系的能力)在早期发育的短暂窗口中作为有序的连续体存在。多能性连续体两侧的两种状态(幼稚和引发)在体外分别被捕获为胚胎干细胞(ESC)和外胚层干细胞(EpiSC)。然而,缺乏稳定的多能干细胞(PSC)来模拟幼稚多能性和引发多能性之间的间隔。
概述
本公开内容至少部分基于以下令人惊讶的发现,即同时激活FGF、TGF-β/Smad和WNT/β-连环蛋白信号传导途径的培养条件能够直接衍生模拟幼稚和引发多能性之间的间隔的多能干细胞(PSC)。此类PSC在本文中可被称为“形成性PSC”或“中间体PSC”。还已证明,根据本文所述方法产生的形成性PSC与小鼠胚胎第5-6天(E5-6)外胚层共有转录组学相似性,并保留了在体外的直接原始生殖细胞(PGC)诱导和在体内的种系嵌合体形成的高能力。
因此,本文提供了用于产生形成性多能干细胞(PSC)的方法,以及包含这种细胞的体外培养系统。由此产生的形成性PSC可以分化成任何类型的细胞(例如,心肌细胞或神经元)。
在一些实施方案中,本公开内容提供了一种用于产生形成性胚胎干细胞(ESC)的方法,该方法包括(i)获得生殖细胞群,和(ii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基中培养该生殖细胞群,从而产生形成性ESC。
在一些实施方案中,生殖细胞群包括囊胚。在一些实施方案中,生殖细胞群获自受试者。在一些实施方案中,受试者选自人、啮齿类动物和有蹄类动物。
在一些实施方案中,FGF激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,FGF激活剂是FGF蛋白。
在一些实施方案中,TGF-β激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,TGF-β激活剂是TGF-β蛋白。在一些实施方案中,TGF-β激活剂是激活素A蛋白。
在一些实施方案中,WNT激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,WNT激活剂是WNT蛋白。在一些实施方案中,WNT激活剂是GSK3抑制剂和/或MEK抑制剂。在一些实施方案中,GSK3抑制剂是CHIR99021。
在一些实施方案中,步骤(ii)进行1至8天。在一些实施方案中,在步骤(ii)之前,将生殖细胞群培养在包含至少一种额外因子的培养基中。
在一些实施方案中,步骤(ii)中的培养基进一步包含至少一种额外因子。在一些实施方案中,至少一种额外因子是MEK抑制剂、胎牛血清(FBS)、白血病抑制因子(LIF)、JNK抑制剂或其组合。在一些实施方案中,MEK抑制剂是PD0325901。在一些实施方案中,JNK抑制剂是SP600125。
在一些实施方案中,在至少一种分化因子的存在下培养在步骤(ii)中产生的形成性ESC。在一些实施方案中,至少一种分化因子选自生长因子、WNT抑制剂、JNK抑制剂和TGF-β抑制剂。在一些实施方案中,生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。在一些实施方案中,WNT抑制剂是IWP2。在一些实施方案中,TGF-β抑制剂是SB431542。在一些实施方案中,JNK抑制剂是SP600125。
在一些实施方案中,本公开内容提供了一种用于产生形成性诱导多能干细胞(iPSC)的方法,该方法包括(i)获得体细胞群,(ii)在包含调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达的重编程剂的第一培养基中培养体细胞群,和(ii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养体细胞群,从而产生形成性iPSC。
在一些实施方案中,体细胞群包括胚胎成纤维细胞。在一些实施方案中,体细胞群获自受试者。在一些实施方案中,受试者选自灵长类动物、啮齿类动物和有蹄类动物。
在一些实施方案中,重编程剂包含核酸。在一些实施方案中,核酸编码重编程基因。在一些实施方案中,核酸编码靶向重编程基因的干扰RNA。在一些实施方案中,核酸包含在载体中。在一些实施方案中,载体是附加型载体。
在一些实施方案中,FGF激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,FGF激活剂是FGF蛋白。
在一些实施方案中,TGF-β激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,TGF-β激活剂是TGF-β蛋白。在一些实施方案中,TGF-β激活剂是激活素A蛋白。
在一些实施方案中,WNT激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,WNT激活剂是WNT蛋白。在一些实施方案中,WNT激活剂是GSK3抑制剂。在一些实施方案中,GSK3抑制剂是CHIR99021。
在一些实施方案中,步骤(ii)进行1至6天。在一些实施方案中,步骤(iii)进行1至8天。
在一些实施方案中,在至少一种分化因子的存在下培养在步骤(iii)中产生的形成性iPSC。
在一些实施方案中,至少一种分化因子选自生长因子、WNT抑制剂、JNK抑制剂和TGF-β抑制剂。在一些实施方案中,生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。在一些实施方案中,WNT抑制剂是IWP2。在一些实施方案中,TGF-β抑制剂是SB431542。在一些实施方案中,JNK抑制剂是SP600125。
在一些实施方案中,本公开内容提供了一种体外培养系统,其包含(a)细胞群,和(b)培养基,该培养基包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂。
在一些实施方案中,体外培养系统进一步包含重编程剂,其调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达。
在一些实施方案中,细胞群包括生殖细胞或体细胞。在一些实施方案中,细胞群包括囊胚或胚胎成纤维细胞。
在一些实施方案中,生殖细胞群获自受试者。在一些实施方案中,受试者选自灵长类动物、啮齿类动物和有蹄类动物。
在一些实施方案中,FGF激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,FGF激活剂是FGF蛋白。
在一些实施方案中,TGF-β激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,TGF-β激活剂是TGF-β蛋白。在一些实施方案中,TGF-β激活剂是激活素A蛋白。
在一些实施方案中,WNT激活剂选自蛋白质、核酸、小分子及其组合。在一些实施方案中,WNT激活剂是WNT蛋白。在一些实施方案中,WNT激活剂是GSK3抑制剂。在一些实施方案中,GSK3抑制剂是CHIR99021。
在一些实施方案中,该培养基还包含至少一种额外的因子。在一些实施方案中,至少一种额外因子是MEK抑制剂、胎牛血清(FBS)、白血病抑制因子(LIF)、JNK抑制剂或其组合。在一些实施方案中,MEK抑制剂是PD0325901。在一些实施方案中,JNK抑制剂是SP600125。
在一些实施方案中,培养基还包含至少一种分化因子。在一些实施方案中,至少一种分化因子选自生长因子、WNT抑制剂和TGF-β抑制剂。在一些实施方案中,生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。在一些实施方案中,WNT抑制剂是IWP2。在一些实施方案中,TGF-β抑制剂是SB431542。
在一些实施方案中,本公开内容提供了一种用于产生形成性胚胎干细胞(ESC)的方法,该方法包括(i)从小鼠获得生殖细胞群,(ii)在包含MEK抑制剂的第一培养基中培养生殖细胞群,和(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性小鼠ESC。
在一些实施方案中,本公开内容提供了一种用于产生形成性胚胎干细胞(ESC)的方法,该方法包括(i)从马获得生殖细胞群,(ii)首先在包含胎牛血清(FBS)、成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基中培养生殖细胞群,以及(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性马ESC。
在一些实施方案中,本公开内容提供了一种用于产生形成性胚胎干细胞(ESC)的方法,该方法包括(i)从猪获得生殖细胞群,(ii)首先在包含胎牛血清(FBS)、成纤维细胞生长因子(FGF)激活剂、白血病抑制因子(LIF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基中培养生殖细胞群,和(iii)在包含成纤维细胞生长因子(FGF)激活剂、白血病抑制因子(LIF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性猪ESC。
在一些实施方案中,本公开内容提供了一种用于产生形成性诱导多能干细胞(iPSC)的方法,该方法包括:(i)从人获得体细胞群,(ii)在包含重编程剂的第一培养基中培养体细胞群,所述重编程剂调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达,和(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂、JNK抑制剂和WNT激活剂的第二培养基中培养体细胞群,从而产生形成性人iPSC。
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本专利或申请文件至少包含一张彩色绘图。带有彩色附图的本专利或专利申请公开的副本将在请求和支付必要费用后由美国专利局提供。
图1A-1N包括显示小鼠FTW-ESC的衍生和表征的数据。图1A包括从小鼠囊胚衍生FTW-ESC的示意图。图1B包括代表性相差图像,显示了用CHIR99021(左,第40代)和500ng/mLWnt3a(右,第7代)衍生的FTW-ESC的典型集落形态。比例尺,100um。图1C包括显示FTW-ESC(第20至30代)生长曲线的图(平均值±标准偏差,n=6,生物学重复)。图1D包括显示使用和不使用ROCK抑制剂Y27632处理的FTW-ESC(第20至30代)的单细胞克隆效率的图(平均值±SD,n=3,生物学重复,N.S.,不显著)。图1E包括第16代的FTW-ESC的代表性免疫荧光(IF)图像。比例尺,100um。图1F包括慢细胞计数结果,显示SOX2和KLF4在FTW-ESC中的均匀表达(第20至30代)(平均值±SD,n=3,生物学重复)。图1G包括显示雌性ESC、FTW-ESC和EpiSC中的Xist RNA FISH信号的图像。比例尺,100um。图1H包括一个直方图,显示在FTW-ESC到EpiSC过渡期间具有Xist FISH信号的细胞的增加的百分比(平均值±SD,n=3,生物学重复)。图1I包括显示X-EGF PFTW-ESC的流式细胞术分析的图。图1J包括显示紧密连接的图像,如通过在ESC、FTW-ESC和EpiSC中的ZO1 IF可视化的。比例尺,100um。图1K包括显示ESC、FTW-ESC和EpiSC中紧密连接相关Claudin家族基因的相对表达水平的图(平均值±SD,n=4,生物学重复,*p<0.05,**p<0.01,***p<0.001)。图1L包括代表性的合并FL和BF图像,显示Oct4-DE-EGFP在ESC、FTW-ESC和EpiSC中的表达模式。比例尺,100um。图1M包括流式细胞术结果图,显示Oct4-DE-EGFP信号强度和ESC、FTW-ESC和EpiSC中的细胞计数。图1N包括来自ESC、FTW-ESC和EpiSC的RNA-seq数据的PCA图。还参见图8和图9。
图2A-2G包括显示FTW-ESC共有形成性多能性特征但不同于EpiLC的数据。图2A包括来自体外(ESC、ASC、RSC、EPS-Deng、EPS-Liu、FTW-ESC、EpiLC和EpiSC)和体内(E2.5分裂球、E3.5和E4.5 ICM和E5.5-E7.5外胚层)样品的RNA-seq数据的PCA图。图2B包括来自ESC、FTW-ESC、EpiSC和48h EpiLC的H3K4me3和H3K27me3 ChIP-seq数据的PCA图。图2C包括显示FTW-ESC相对ESC(ESC.Bao)中每个基因的平均FPKM值针对倍数变化的MA图。显示了下面列出的选定的幼稚和形成性基因的基因符号。图2D包括IGV基因组浏览器视图,显示ESC和FTW-ESC中代表性形成性基因和幼稚基因的H3K4me3和H3K27me3修饰。图2E包括VENN图(左),显示ESC、FTW-ESC和EpiSC中常见和差异表达的转录因子和辅因子的数量(与MEF相比,FC>2和P<0.05),以及在FTW-ESC中特别上调的79个TF和辅助因子的前8个富集GO项的图(右)。图2F包括第2天在3D Matrigel条件下培养的GPI-EGFP标记的ESC、FTW-ESC和EpiSC的代表性FL图像。比例尺,100um。图2G包括显示在图2F中所示的第1天和第2天的不同类型结构(杂乱无章、玫瑰花结和管腔)的比率的图。还参见图10。
图3A-3K包括显示FTW-ESC表现出嵌合体和PGC双重能力的数据。图3A包括显示FTW-ESC的嵌合贡献和分化的代表性IF图像。用GFP抗体染色的EGFP、FTW-ESC衍生物;谱系标志物,谱系标志物:NESTIN,外胚层;cTNT,中胚层;和FOXA2,内胚层。右侧显示了合并图像(使用DAPI)和框出区域的更高放大倍数的图像。比例尺,100mm。图3B包括显示通过将C57BL/6FTW-ESC注射到B6-albino(B6(Cg)-Tyrc-2J/J宿主囊胚中产生的毛色嵌合体(黄色箭头)的图像。图3C包括显示在第5代由ESC和FTW-ESC生成的毛色嵌合体的比率的图,活体幼崽总数(n)显示在图中。图3D包括显示FTW-ESC衍生嵌合体的种系传递的图像。雌性:WT,B6-albino。雄性:B6(FTW-ESC)/B6-albino嵌合体。图3E包括显示使用FGFR抑制剂(PD173074)从FTW-ESC诱导的第2天、第4天和第6天PGC-LC的代表性FL图像(通过Blimp1-mVenus(BV)和Stella-ECFP(SC)表达可视化)。比例尺,100um。图3F包括显示在FTW-ESC的PGC-LC诱导2、4和6天后的BV/SC表达的FACS分析的数据。图3G包括显示从FTW-ESC诱导PGC-LC期间基因表达动态的数据。(平均值±SD,n=3)。黑线:BV和SC双阳性细胞,灰色虚线:BV和SC双阴性细胞。图3H包括从FTW-ESC诱导的PGC-LC的代表性IF(TFAP2C和BLIMP1)图像。插图是框出区域的更高放大倍率图像。比例尺,100um。图3I包括FTW-ESC的PGC-LC诱导6天后5mC的代表性IF图像。虚线描绘了5mC信号减少的细胞(PGC-LC由BLIMP1染色标记)。比例尺,100um。图3J-3K包括FTW-ESC的PGC-LC诱导6天后H3K9me2(图3J)和H3K27me3(图3K)的代表性IF图像。插图是框出区域的更高放大倍率图像。比例尺,100um。还参见图11。
图4A-4M包括显示马FTW-PSC的衍生和表征的数据。图4A包括源自马囊胚和胚胎成纤维细胞的FTW-eqPSC的示意图。图4B包括在MEF饲养层和无饲养层条件(Matrigel,MG)上生长的马囊胚和FTW-eqESC(第23代)的代表性BF图像。比例尺,100μm。图4C包括在MEF饲养层和无饲养层条件(MG)上生长的马胚胎成纤维细胞和FTW-eqiPSC(第38代)的代表性BF图像。比例尺,100μm。图4D包括显示使用质粒特异性引物进行基因组PCR的数据,显示所有外源重编程因子在两个独立的FTW-eqiPSC系中传代20次后被沉默。图4E包括代表性IF图像,显示FTW-eqESC(第19代)表达多能性标志物(SOX2和OCT4)但不表达胚胎外谱系标志物(TE、EMOES;PE、GATA6)。比例尺,100μm。图4F包括流式细胞术结果,表明大多数FTW-eqiPSC表达OCT4和SOX2。图4G包括显示FTW-eqESC(顶部)和FTW-eqiPSC(底部)碱性磷酸酶(AP)染色的图像。比例尺,100μm。图4H包括显示FTW-eqPSC生长曲线的图(两个FTW-eqESC系(第10-20代)和两个FTW-eqiPSC系(第20-30代))。图4I包括显示使用和不使用ROCK抑制剂Y27632处理的FTW-eqPSC(两个FTW-eqESC系和两个FTW-eqiPSC系)的单细胞克隆效率的图(平均值±SD,n=3,生物学重复,N.S.=无显著性)。图4J包括显示FTW-eqiPSC、FTW-eqESC和体内马样品(Eq-ICM、Eq-EEF和Eq-TE)的层次聚类和相关性分析的图。所有检测到的基因的表达水平(FPKM)用于绘制此图。图4K包括显示FTW-eqPSC中选定多能性基因的RNA-seq、H3K4me3和H3K27me3轨迹的图。图4L包括显示FTW-eqiPSC胚状体(EB)分化为外胚层(TUJ1)、中胚层(cTnT)和内胚层(AFP)谱系的代表性IF图像。比例尺,100μm。图4M包括代表性的H&E染色图像,显示由FTW-eqiPSC形成的畸胎瘤,其中包含来自所有三个胚胎胚层的组织。还参见图12。
图5A-5I包括显示FTW-eqPSC具有小鼠形成特征并且具有嵌合体和PGC双重能力的数据。图5A包括代表性BF和IF图像,显示mKO标记的FTW-eqiPSC植入马ICM并在体外(2DIV)胚胎培养2天后表达OCT4。右侧显示了框出区域的更高放大倍率图像。比例尺,100um。图5B包括代表性FL图像,显示小鼠、绵羊、山羊和猪囊胚(BL)中mKO标记的FTW-eqiPSC的ICM掺入。红色,mKO标记的FTW-eqiPSC。图5C包括显示EGFP标记的FTW-eqESC对E9.5小鼠胚胎(嵌合体#1)的种间嵌合体贡献的代表性图像。左,WT对照。右,马小鼠嵌合胚胎。图5D包括代表性免疫荧光图像,显示FTW-eqESC(嵌合体#1)的种间嵌合体贡献和分化。用GFP抗体染色的EGFP、FTW-eqESC衍生物;谱系标志物:TuJ1,外胚层;SMA,中胚层;和FOXA2,内胚层。右侧显示了合并图像(使用DAPI)和框出区域的更高放大倍数的图像。比例尺,100mm。图5E包括来自小鼠(mESC、XPSC、mEpiLC和mEpiSC)和马(Eq-ICM、FTW-eqESC和FTW-eqiPSC)样品的RNA-seq数据的PCA图。图5F包括显示从FTW-eqESC直接诱导PGC-LC的图。qRT-PCR结果显示FTW-eqESC诱导3天后PGC-LC标志物的上调(平均值±SD,n=3,生物学重复,*p<0.05,**p<0.01,***p<0.001)。图5G包括从FTW-eqESC诱导PGC-LC3天后TFAP2C、PRDM1和DPPA3的代表性IF图像。比例尺,100um。图5H包括Nanos3-EGFP-KI报告因子FTW-ESC系(顶部)的生成策略示意图,以及显示从Nanos3-EGFP-KI FTW-eqESC的第1天、第2天和第3天PGC-LC诱导的代表性图像(底部)。图5I包括来自Nanos3-EGFP-KI FTW-eqESC的未诱导和PGC-LC诱导后1、2和3天的EGFP表达的FACS分析数据。还参见图13。
图6A-6J包括显示人FTW-iPSC的衍生和表征的数据。图6A包括从人成纤维细胞产生FTW-hiPSC的示意图。图6B包括一个代表性的BF图像,显示了FTW-hiPSC的典型集落形态(第31代)。比例尺,100um。图6C包括代表性IF图像,显示FTW-hiPSC(第26代)表达的核心多能性标志物(SOX2和OCT4)和形成性多能性标志物OTX2。比例尺,100um。图6D包括代表性的IF图像,显示幼稚(SUSD2和KLF17)和引发的(CD24)多能性标志物未在FTW-hiPSC中表达。幼稚hESC在5iLA条件下培养。在NBFR条件下培养引发的hiPSC。比例尺,100um。图6E包括显示大多数FTW-hiPSC表达OTX2但不表达CD24的流式细胞术结果。图6F包括显示在第20-30代的FTW-hiPSC和引发的hiPSC(NBFR条件)的倍增时间的直方图(平均值±SD,n=3,生物学重复,*p<0.05)。图6G包括使用和不使用ROCK抑制剂Y27632处理的FTW-hiPSC和引发的hiPSC(NBFR条件)的单细胞克隆效率图(平均值±SD,n=3,生物学重复,***p<0.001,N.S.=无显著性)。图6H包括来自幼稚hESC(5iLA和重置条件)、FTW-hiPSC和引发的hESC的RNA-seq数据的PCA图。图6I包括热图分析,显示936个基因在FTW-hiPSC中与幼稚和引发的hESC相比特异性上调。图6J包括显示图6I中的936个FTW-hiPSC特异性基因的GO分析的数据。还参见图14。
图7A-7F包括显示FTW-eqPSC具有小鼠形成性特征并且具有PGC和嵌合体双重能力的数据。图7A包括来自体外(重置、HNES、5/6iLA、4i、FTW-hiPSC、2iLI、NHSM、2iLIF和引发的hESC)和体内(人E6、E8、E10和E12外胚层)样品的RNA-seq数据的PCA图。图7B包括显示FTW-hiPSC相对幼稚hESC(重置和5iLA)中每个基因的平均FPKM值针对倍数变化的MA图。显示选定的幼稚(红色)和形成性(绿色)基因的基因符号。图7C包括显示FTW-hiPSC的PGC-LC诱导2、4和6天后两种人PGC相关表面标志物(Ep-CAM和CD49f)表达的FACS分析的数据。图7D包括显示来自FTW-hiPSC的PGC-LC诱导期间的基因表达动力学的数据。(平均值±SD,n=3)。黑线:Ep-CAM和CD49f双阳性细胞,灰色虚线:Ep-CAM和CD49f双阴性细胞。图7E包括从FTW-hiPSC诱导的PGC-LC的代表性IF(TFAP2C、PRDM1和NANOS3)图像。比例尺,100um。图7F包括形成性类似的XPSC的总结图。还参见图14。
图8A-8I包括显示小鼠FTW-ESC的衍生和表征的数据。图8A包括该方法的示意图和代表性BF图像,显示从E3.5囊胚的小鼠FTW-ESC衍生。比例尺,100um。图8B包括显示第16代的雌性(左)和雄性(右)FTW-ESC系的核型分析的数据。图8C包括显示ESC、FTW-ESC和EpiSC中核心、幼稚和引发多能性基因的相对表达水平的数据(平均值±SD,n=3,生物学重复,*p<0.05,**p<0.01,***p<0.001)。图8D包括显示ESC、FTW-ESC和EpiSC中TOPFlash和FOPFlash报告因子活性的直方图。(平均值±SD,n=4,生物学重复)。图8E包括显示ESC(在供应有CHIR99021、PD0325901和LIF的N2B27培养基N2B27-2iL中培养)、FTW-ESC(在供应有FGF2、激活素A和CHIR99021的N2B27培养基N2B27-FAC中培养)和EpiSC(在供应有FGF2和IWR1的N2B27培养基N2B27-FR中培养)中FGF/Erk和TGF-β/Smad途径激活状态的分析的数据。代表性蛋白质印迹显示磷酸化MAPK和Smad2/3(P-MAPK和P-Smad2/3)以及MAPK和Smad2/3的总蛋白水平。黏着斑蛋白用作上样对照。图8F包括qRT-PCR结果的热图,显示2代后在不同FTW培养基中培养的FTW-ESC的表达模式。WNT3a-L(50ng/ml);WNT3a-H(500ng/ml)。图8G包括2代后在不同FTW培养基中培养的FTW-ESC的代表性合并IF图像。比例尺,50um。图8H包括显示图8G中所示的OCT4和SOX2阳性(或阴性)细胞的比率的数据。图8I包括在从第1代(P1)到第4代(P4)的每个代中在FT、FW、TW和FTW培养基中培养的FTW-ESC中核心多能性(Pou5f1和Sox2)、幼稚(Nanog和Klf4)、引发(Otx2和Dnmt3b)和谱系标志物(Sox1、Gata4和Gata6)的qRTPCR结果(n=3,生物学重复)。
图9A-9G包括显示小鼠FTW-ESC共有幼稚和引发的PSC的特征的数据。图9A包括显示FTW-ESC和EpiSC可以通过培养适应从ESC连续转化的图像。比例尺,100um。图9B包括XistRNA FISH染色的代表性图像,显示在FTW-ESC到EpiSC的转化过程中具有阳性Xist信号的细胞数量增加。比例尺,100um。图9C包括代表性的FL和BF图像,显示在FTW-ESC到EpiSC的转化过程中具有阳性X-EGFP信号的细胞数量减少。比例尺,100um。图9D包括图9C中X-EGFP信号的FACS分析图。图9E包括图2E中所示的ESC、FTW-ESC和EpiSC中Oct4-DE-EGFP阳性集落的比例的图。图2F包括显示296个多能性相关基因在ESC、FTW-ESC和EpiSC中的差异表达的热图。图9G包括显示ESC、FTW-ESC和EpiSC中的H3K4me3和H3K27me3 ChIP-seq信号的数据。
图10A-10F包括显示FTW-ESC共有形成性多能性的特征的数据。图10A包括显示FTW-ESC中2783个H3K4me3-高基因的GO分析的数据。图10B包括显示FTW-ESC中2215个H3K27me3-高基因的GO分析的数据。图10C包括从RNA-seq数据集中选择的参与糖酵解和三羧酸循环的线粒体复合物COX和酶的基因倍数变化的热图(与ESC相比)。图10D包括显示FTW-ESC相对EpiLC(48h)中平均FPKM值相对于每个基因的倍数变化的MA图。显示了选定的幼稚基因、形成性基因和引发基因的基因符号。图10E包括IGV基因组浏览器视图,显示FTW-ESC和EpiLC(48h)中代表性幼稚和形成性基因的H3K4me3和H3K27me3轨迹。图10F包括显示NANOG、OTX2、OCT4和GAPDH(上样对照)蛋白在FTW-ESC和EpiLC(48h)中的表达的蛋白质印迹图像。
图11A-11E包括显示FTW-ESC表现出嵌合体和PGC双重能力的数据。图11A包括从FTW-ESC生成的嵌合体中的谱系标志物的代表性IF图像。用GFP抗体染色的FTW-ESC衍生物;谱系标志物:TuJ和PAX6,外胚层;SMA和T,中胚层;AFP和SOX17,内胚层。右侧显示了合并图像(使用DAPI)和框出区域的更高放大倍数的图像。比例尺,100mm。图11B包括显示Oct4-DE-EGF PFTW-ESC对E13.5小鼠性腺的嵌合贡献的代表性图像。G:性腺,M:中肾。图11C包括代表性FL图像,显示FTW-ESC的第2、4和6天PGC-LC诱导,其通过Blimp1-mVenus(BV)和Stella-ECFP(SC)表达可视化。比例尺,100um。图11D包括代表性图像(顶部)和直方图(底部),显示在用不同途径抑制剂处理的PGC-LC诱导4天后BVSC阳性和/或阴性细胞的比率。图11E包括显示来自具有或不具有FGF抑制剂PD173074的从头衍生的FTW-ESC的PGC-LC诱导效率的直方图。
图12A-12O包括显示马FTW-PSC的衍生和表征的数据。图12A-12B包括FTW-eqESC(图12A)和FTW-eqiPSC(图12B)衍生的示意图。图12C包括显示EGFP附加型载体在长期传代(P20)后逐渐沉默的数据。对FTW-eqiPSC进行EGFP表达成像,并在第5、10、15和20代时通过流式细胞术进行分析。图12D包括显示在指示的传代的两个FTW-eqiPSC系中所有四个附加型载体的总拷贝数的图。图12E包括显示外源重编程因子沉默之前(<15代)和之后(>20代)两个FTW-eqiPSC系的倍增时间的图(平均值±SD,n=7,生物学重复)。图12F包括来自外源重编程因子沉默之前(第5代)和之后(第20代)两个FTW-eqiPSC系的细胞周期分析的数据。图12G包括来自使用马特异性引物的RT-PCR的数据,显示马内源多能性基因在FTW-eqESC和FTW-eqiPSC中表达。图12H包括来自FTW-eqPSC(两个FTW-eqESC系和两个FTWeqiPSC系)的染色体分析的数据。图12I-12J包括eqESC、FTW-eqiPSC和eq-ICM中1798个通常上调基因的热图(图12I)和GO分析(图12J)。图12K包括来自FTWeqESC和FTW-eqiPSC中全局H3K4me3和H3K27me3 ChIP-seq信号的数据。图12L包括从FTW-eqiPSC定向分化心肌细胞的实验计划示意图,以及FTW-eqiPSC衍生的心肌细胞的代表性BF图像(右)。比例尺,100um。图12M包括FTW-eqiPSC衍生的心肌细胞的代表性IF图像。比例尺,100um。图12N包括从FTW-eqiPSC定向神经元分化的实验计划示意图,以及FTW-eqiPSC衍生的神经元的代表性BF图像(右)。比例尺,100um。图12O包括FTW-eqiPSC衍生的神经元谱系的代表性IF图像。比例尺,100um。
图13A-13L包括显示FTW-eqPSC具有小鼠形成性特征并且具有嵌合体和PGC双重能力的数据。图13A包括代表性IF图像,显示mKO标记的FTW-eqiPSC移植到小鼠、猪和绵羊ICM中并且在体外胚胎培养3天(3DIV)后表达OCT4(小鼠)或SOX2(猪和绵羊)。比例尺,100um。图13B包括代表性的BF和IF图像,显示mKO标记的FTW-eqiPSC植入到植入后小鼠外胚层并在体外胚胎培养6天(6DIV)后表达OCT4。框出区域的更高放大倍率图像显示在底部。图13C包括显示EGFP标记的FTW-eqESC对E7.75小鼠胚胎的种间嵌合体贡献的代表性图像。左,WT对照。右,马小鼠嵌合胚胎。图13D包括显示EGFP标记的FTW-eqESC对E9.5小鼠胚胎的种间嵌合体贡献的代表性图像(嵌合体#2)。左,WT对照。右,马小鼠嵌合体胚胎。图13E包括代表性免疫荧光图像,显示FTW-eqESC(嵌合体#2)的种间嵌合体贡献和分化。用GFP抗体染色的FTW-eqESC衍生物;谱系标志物:TuJ1,外胚层;SMA,中胚层;和FOXA2,内胚层。右侧显示了合并图像(使用DAPI)和框出区域的更高放大倍数的图像。比例尺,100mm。图13F包括显示小鼠(ESC、EpiLC和EpiSC)和马(Eq-ICM、FTW-eqESC和FTW-eqiPSC)样品中1,619个引发多能性相关基因的倍数变化的热图。黑色和灰色分别表示log2转换后的倍数变化<0和>0。图13G包括使用马特异性引物的RT-PCR结果图像,显示几种小鼠形成性多能性基因在FTW-eqESC和FTWeqiPSC中表达。图13H包括显示选定的形成性多能性相关基因的基因表达水平、H3K4me3和H3K27me3修饰的IGV基因组浏览器视图。图13I包括第2天在3D Matrigel条件下培养的FTW-eqESC的代表性IF(鬼笔环肽)图像。比例尺,100um。图13J包括通过FTW-eqESC中的ZO1免疫染色显示的紧密连接的代表性图像。比例尺,100um。图13K包括Nanos3-EGFP-KI报告因子FTW-eqESC系生成策略的示意图。图13L包括显示在不同途径抑制剂的存在下第4天PGC-LC诱导效率的直方图。
图14A-14G包括显示人FTW-iPSC的表征和跨物种比较的数据。图14A包括显示FTW-hiPSC_#2中指定传代(P12、P25和P33)的附加型载体的总拷贝数的图。ENBA(Epstein-Barr核抗原-1)序列用于检测附加型载体。图14B包括代表性的H&E染色图像,显示由FTW-hiPSC_#2(第30代)形成的畸胎瘤包含来自所有三个胚胎胚层的组织。图14C包括显示紧密连接的代表性图像,如通过FTW-hiPSC中的ZO1免疫染色所显示的。比例尺,100um。图14D包括第2天在3D Matrigel条件下培养的FTW-hiPSC的代表性IF(鬼笔环肽)图像。比例尺,100um。图14E包括显示在不同途径抑制剂(FGF、TGFβ、WNT或LIF抑制剂)的存在下从人FTW-iPSC的人PGC-LC诱导效率的图。图14F包括来自FTW-mESC、FTW-eqESC/iPSC和FTW-hiPSC的层次聚类和相关分析的数据。所有检测到的基因的表达水平(FPKM)用于绘制此图。图14G包括人(n=1220)、马(n=1269)和小鼠XPSC(n=1540)的物种特异性基因的热图和GO分析。
图15A-C包括显示在SP600125(JNK抑制剂)的存在下人FTW-iPSC的分化和生长的数据。图15A包括提供有SP600125(JNK抑制剂)的人FTW-iPSC的代表性明场图像。图15B包括显示在不存在不同浓度的SP600125(JNK抑制剂)的情况下的倍增时间的图。图15C包括代表性免疫荧光图像,显示提供有SP600125的人FTW-iPSC表达多能性标志物(SOX2和OCT4)。比例尺,100μm。图15D-E显示了显示根据本公开内容的方法产生的分化的白犀牛FTWi-iPSC的数据。图15D包括犀牛FTW-iPSC的代表性明场图像。比例尺,100μm。图15E包括代表性免疫荧光图像,显示犀牛FTW-iPSC表达的多能性标志物(SOX2和OCT4)。比例尺,100μm。图15F-15G显示了根据本公开内容的各种方法制备的分化的猪FTW-PSC。图15F包括猪FTW-ESC的代表性明场图像。比例尺,100μm。图15G包括显示猪FTW-ESC表达的多能性标志物(SOX2和OCT4)的代表性免疫荧光图像。比例尺,100μm。
本发明的一个或多个实施方案的细节在下面的描述中阐述。本发明的其他特征或优点将从以下附图和几个实施方案的详细描述以及所附权利要求中变得明显。
详细描述
动态多能干细胞(PSC)状态代表体内多能性连续体的体外适应。多能性连续体两侧的两种状态(幼稚和引发)在体外分别被捕获为胚胎干细胞(ESC)和外胚层干细胞(EpiSC)。“幼稚”小鼠ESC最类似于成熟囊胚的幼稚外胚层(大约胚胎第4天,~E4),而“幼稚”EpiSC显示的基因表达特征更类似于原肠胚晚期胚胎的前外胚层(大约胚胎第7天,~E7)。幼稚多能性和引发多能性之间的多能干细胞(PSC)尚未被捕获,因此它们的转录、表观遗传和功能特征尚不清楚。
本公开内容至少部分基于以下令人惊讶的发现,即同时激活FGF、TGF-β/Smad和WNT/β-连环蛋白信号传导途径的培养条件能够直接衍生模拟幼稚和引发多能性之间的间隔的PSC。此类PSC在本文中可被称为“形成性PSC”(也被称为“中间体PSC”)。根据本文所述方法产生的形成性PSC与第5-6天胚胎(E5-6)外胚层共有转录组学相似性,并保留了体外直接原始生殖细胞(PGC)诱导和体内种系嵌合体形成的高能力。迄今为止,本领域已知的PSC均未证明具有这种体外直接诱导PGC的能力。还已经证明,本文所述的方法可用于为各种物种产生形成性PSC,例如啮齿类动物(小鼠)、有蹄类动物(马)和灵长类动物(人)物种。
因此,本文提供了用于产生形成性多能干细胞(PSC)的方法,以及包含这种细胞的体外培养系统。由此产生的形成性PSC可以分化成任何类型的细胞(例如,心肌细胞或神经元)。
I.产生形成性多能干细胞(PSC)的方法
任何FGF激活剂、TGF-β激活剂和WNT激活剂的组合,例如本文所述的那些,可用于在离体或体外培养中产生形成性多能干细胞(PSC)(例如,胚胎干细胞(ESC)或诱导性多能干细胞(iPSC))。形成性PSC是指存在于幼稚阶段和引发阶段之间的发育连续体中的PSC。因此,形成性PSC可能具有不同于其幼稚和引发对应物的分子特征,例如不同的分子特征(例如,转录和表观遗传特征)和不同的功能特征(例如,嵌合体形成和原始生殖细胞(PGC)特化的双重能力)。
因此,本公开内容提供了通过在存在至少一种FGF激活剂、至少一种TGF-β激活剂以及至少一种WNT激活剂的情况下培养细胞(例如囊胚或胚胎成纤维细胞)来在细胞培养物中产生形成性PSC的培养方法(例如离体培养方法)。由此产生的形成性PSC可以分化成任何类型的细胞(例如,心肌细胞或神经元)。
为了进行本文所述的培养方法,可以从任何合适的来源获得合适的细胞群。在一些实施方案中,细胞群可获自受试者,例如,获自组织(例如,胚胎组织)、骨(例如,骨髓)、血液(例如,外周血或脐带血)、体液(例如,泪液、尿液或唾液)、血清、血浆或蛋白质,通过本领域已知的任何方式从受试者获取。受试者包括但不限于人或非人哺乳动物,例如啮齿类动物(例如,小鼠或大鼠)或有蹄类动物(例如,马或猪)。
任何合适的细胞群均可用于本文所述的产生形成性PSC的方法。在一些实施方案中,细胞群包含生殖细胞,例如雌性种系干细胞及其后代。生殖细胞的实例包括但不限于胚胎、卵母细胞、受精卵、分裂球、桑葚胚和囊胚。
在一些实施方案中,细胞群包括体细胞例如成纤维细胞(例如,胚胎成纤维细胞或皮肤成纤维细胞)。体细胞可以通过众所周知的方法从不同器官(例如皮肤、肺、胰腺、肝、胃、肠、心脏、生殖器官、膀胱、肾、尿道和其他泌尿器官)获得。体细胞的实例包括但不限于成体干细胞、支持细胞、内皮细胞、颗粒上皮细胞、神经元、胰岛细胞、表皮细胞、上皮细胞、肝细胞、毛囊细胞、角质形成细胞、造血细胞、黑素细胞、软骨细胞、淋巴细胞(B淋巴细胞和T淋巴细胞)、红细胞、巨噬细胞、单核细胞、单核细胞、成纤维细胞、心肌细胞和其他肌肉细胞。
可以在存在有效量的至少一种FGF激活剂、至少一种TGF-β激活剂和至少一种WNT激活剂(例如如本文所述的那些)的情况下,在合适的培养基(例如细胞培养基)中培养本文所述的任何细胞群持续合适的时间段,例如至少18小时、至少约24小时、至少36小时、至少48小时、至少60小时、至少72小时、至少84小时、至少96小时、至少约5天、至少约6天、至少约7天、至少约8天或更长。
如本文所用,“有效量”、“有效剂量”或“对......有效的量”指本文所述的FGF激活剂、TGF-β激活剂和WNT激活剂的量,其有效提供形成性PSC的至少一项特征(例如,嵌合体能力、PGC特化反应性和/或多谱系分化潜能)。此类特性可通过常规方法监测或可根据本文描述的方法监测。有效量可以取决于例如使用的FGF激活剂、TGF-β激活剂和WNT激活剂而变化。
例如,用于在本文所述方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致处于多能性形成性阶段的细胞比例与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时处于多能性形成性阶段的细胞的比例相比增加至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
在一些实施方案中,用于在本文所述方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中嵌合体形成效率与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时的嵌合体形成效率相比增加至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
在一些实施方案中,用于在本文所述的方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中原始生殖细胞(PGC)诱导效率与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时的PGC诱导效率相比增加至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
用于在本文所述方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中形成性多能性标志物(例如,本文描述的那些,例如OTX2)的表达与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时形成性多能性标志物的表达相比增加至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
在一些实施方案中,用于在本文所述的方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中核心多能性标志物(例如,本文描述的那些,例如SOX2和OCT4)的表达与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时核心多能性标志物的表达相比增加至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
在一些实施方案中,用于在本文所述的方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中幼稚多能性标志物(例如,本文描述的那些,例如SUSD2和KLF17)的表达与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时幼稚多能性标志物的表达相比减少至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
在一些实施方案中,用于在本文所述的方法中培养细胞群的有效量的FGF激活剂、TGF-β激活剂和WNT激活剂导致细胞群中引发多能性标志物(例如,本文描述的那些,例如CD24)的表达与在没有FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群时引发多能性标志物的表达相比减少至少10%或更多,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多。
用于本文所述的方法的FGF激活剂的有效量可以为0.1至10,000ng/ml。在一些实施方案中,用于本文所述方法的FGF激活剂的有效量可以为1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml、或2,500至5,000ng/ml。
在一些实施方案中,用于本文所述方法的FGF激活剂的有效量可以为0.1至100μM。在一些实施方案中,用于本文所述方法的FGF激活剂的有效量可以为0.1至90μM、0.1至80μM、0.1至70μM、0.1至60μM、0.1至50μM、0.1至40μM、0.1至30μM、0.1至20μM、0.1至10μM、0.1至1μM和0.1至0.5μM。在一些实施方案中,用于本文所述方法的FGF激活剂的有效量可以是0.5至100μM、1至100μM、10至100μM、20至100μM、30至100μM、40至100μM、50至100μM、60至100μM、70至100μM、80至100μM和90至100μM。
用于本文所述方法的有效量的TGF-β激活剂可以为0.1至10,000ng/ml。在一些实施方案中,用于本文所述方法的TGF-β激活剂的有效量可以为1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml。
在一些实施方案中,用于本文所述方法的TGF-β激活剂的有效量可以为0.1至100μM。在一些实施方案中,用于本文所述方法的TGF-β激活剂的有效量可以为0.1至90μM、0.1至80μM、0.1至70μM、0.1至60μM、0.1至50μM、0.1至40μM、0.1至30μM、0.1至20μM、0.1至10μM、0.1至1μM和0.1至0.5μM。在一些实施方案中,用于本文所述方法的TGF-β激活剂的有效量可以为0.5至100μM、1至100μM、10至100μM、20至100μM、30至100μM、40至100μM、50至100μM、60至100μM、70至100μM、80至100μM和90至100μM。
用于本文所述方法的WNT激活剂的有效量可以为0.1至10,000ng/ml。在一些实施方案中,用于本文所述方法的WNT激活剂的有效量可以为1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml。
在一些实施方案中,用于本文所述方法的WNT激活剂的有效量可以为0.1至100μM。在一些实施方案中,用于本文所述方法的WNT激活剂的有效量可以为0.1至90μM、0.1至80μM、0.1至70μM、0.1至60μM、0.1至50μM、0.1至40μM、0.1至30μM、0.1至20μM、0.1至10μM、0.1至1μM和0.1至0.5μM。在一些实施方案中,用于本文所述方法的WNT激活剂的有效量可以为0.5至100μM、1至100μM、10至100μM、20至100μM、30至100μM、40至100μM、50至100μM、60至100μM、70至100μM、80至100μM和90至100μM。
本文描述的方法包括在包含至少一种额外因子(例如MEK抑制剂、生长因子、白血病抑制因子(LIF)、敲除血清替代物(KOSR)、胎牛血清(FBS)、JNK抑制剂或其组合)的培养基中培养任何细胞群。
MEK抑制剂是一种化学物质或药物,其抑制有丝分裂原激活的蛋白激酶激酶MEK1和/或MEK2。它们可用于抑制MAPK/ERK途径。MEK是一种磷酸化丝裂原激活蛋白激酶(MAPK)的激酶。如本文所用,“MEK”是指MEK的任何同种型(例如,MEK1或MEK2)。抑制这些同种型中的一种或两种的抑制剂是有用的。在一些实施方案中,MEK抑制剂特异性抑制MEK并且基本上不抑制大多数其他哺乳动物激酶。
任何MEK抑制剂均可用于本文所述的方法中。示例性的MEK抑制剂包括但不限于GSK1120212、XL518、MEK162、CI-1040、PD0325901和TAK-733。
应当理解,MEK抑制剂应该能够以足够的量进入细胞以抑制其中的MEK,从而产生形成性PSC。在一些实施方案中,MEK抑制剂以至少等于MEK抑制剂的IC50的浓度添加到细胞培养基中。在一些实施方案中,MEK抑制剂以MEK抑制剂IC50的0.5至50倍的浓度添加到细胞培养基中。
在一些实施方案中,MEK抑制剂(例如,PD0325901)以0.1至100μM的浓度添加到细胞培养基中。在一些实施方案中,将MEK抑制剂(例如,PD0325901)以0.1至90μM、0.1至80μM、0.1至70μM、0.1至60μM、0.1至50μM、0.1至40μM、0.1至30μM、0.1至20μM、0.1至10μM、0.1至1μM和0.1至0.5μM的浓度添加到细胞培养基中。在一些实施方案中,将MEK抑制剂(例如,PD0325901)以0.5至100μM、1至100μM、10至100μM、20至100μM、30至100μM、40至100μM、50至100μM、60至100μM、70至100μM、80至100μM和90至100μM的浓度添加到细胞培养基中。
白血病抑制因子(LIF)属于白介素6细胞因子家族。LIF与由低亲和力LIF受体和gp130组成的异二聚体受体结合,下游信号传导通过gp130传递。gp130下游有许多信号传导途径,包括STAT3、磷脂酰肌醇3激酶(PI3K)和Ras/Erk途径。
在一些实施方案中,LIF蛋白被添加到培养基中。在一些实施方案中,LIF蛋白以0.1至10,000ng/ml(例如,10ng/ml)的浓度添加至细胞培养基。在一些实施方案中,将LIF蛋白以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
敲除血清替代物(KOSR)是一种成分明确的无血清制剂,其经过优化以在培养物中生长和维持未分化的胚胎干细胞。它比胎牛血清更稳定,质量更一致,并且在维持胚胎干(ES)细胞和诱导多能干(iPS)细胞的未分化状态方面表现更好。
在一些实施方案中,KOSR被添加到培养基中。在一些实施方案中,将KOSR以0.1至20%(例如,10%)的浓度添加到细胞培养基中。在一些实施方案中,将KOSR以0.1%至15%、0.1%至10%、0.1%至5%、0.1%至1%、0.1%至0.5%、0.5%至20%、1%至20%、5%至20%、10%至20%和15%至20%的浓度添加到细胞培养基中。
胎牛血清(FBS)是来自胎牛的凝血的液体部分,不含细胞、纤维蛋白和凝血因子,但含有细胞生长所必需的大量营养和大分子因子。牛血清白蛋白是FBS的主要成分。FBS中的生长因子对于培养的细胞的维持和生长至关重要。FBS还含有多种小分子,如氨基酸、糖类、脂质和激素。
在一些实施方案中,将FBS添加到培养基中。在一些实施方案中,将FBS以0.1至20%(例如,10%)的浓度添加至细胞培养基。在一些实施方案中,将FBS以0.1%至15%、0.1%至10%、0.1%至5%、0.1%至1%、0.1%至0.5%、0.5%至20%、1%至20%、5%至20%、10%至20%和15%至20%的浓度添加到细胞培养基中。
C-JUN N末端激酶(JNK)属于丝裂原激活蛋白激酶(MAPK)家族,其介导细胞对各种类型的细胞外应激损伤的反应。它们调节诸如胚胎发育和组织再生的生理过程,在细胞增殖和程序性细胞死亡中发挥作用。
在一些实施方案中,将有效量的JNK抑制剂添加到培养基中。在一些方面,用于在本文描述的方法中培养细胞群的有效量的JNK抑制剂导致多能细胞的生长增加。这种增加的生长可以被观察为例如多能细胞群的倍增时间的减少。在一些实施方案中,将JNK抑制剂以约0.1μM至约20μM、约0.1μM至约15μM、约0.1μM至约10μM、约0.1至约5μM、约0.5μM至约20μM、约0.5μM至约15μM、约0.5μM至约10μM或约0.5μM至约5μM的浓度添加到培养基中。在一些实施方案中,JNK抑制剂以约0.1μM至约20μM的浓度添加到培养基中。在一些实施方案中,JNK抑制剂可包含SP600125。
可以在至少一种额外因子和FGF激活剂、TGF-β激活剂和WNT激活剂的存在下培养细胞群。或者,或另外地,在存在FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群之前和/或之后,可以在存在至少一种额外因子的情况下培养细胞群。
例如,在存在FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群体之前,可以在存在MEK抑制剂(例如,PD0325901)的情况下培养细胞群。在另一个实例中,细胞群可以在FBS、FGF激活剂、TGF-β激活剂和WNT激活剂的存在下培养。在另一个实例中,可以在存在LIF蛋白、FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群。在另一个实例中,细胞群可以在FBS、LIF蛋白、FGF激活剂、TGF-β激活剂和WNT激活剂的存在下培养。在又一实例中,在存在FGF激活剂、TGF-β激活剂和WNT激活剂的情况下培养细胞群之后,可以在存在JNK抑制剂(例如,SP600125)的情况下培养细胞群。
本文所述的方法涵盖本文所述的任何细胞群的遗传操作。遗传操作包括修饰、插入或删除细胞中的至少一个基因。
遗传操作可以包括用载体转导,例如非整合载体(例如附加型载体)或整合载体(例如慢病毒载体)。在一些实施方案中,本文所述的方法涉及使用附加型载体对细胞群进行遗传操作。因此,在一些实施方案中,本文所述方法中涉及的细胞群是遗传修饰的细胞。
如本文所用,“载体”是能够促进核酸分子转移到细胞中的任何核酸载体(DNA或RNA)。一般而言,载体包括但不限于附加型载体、质粒、噬菌粒、病毒载体和源自病毒或细菌来源的已通过插入或掺入靶核苷酸序列进行操作的其他载体。病毒载体包括但不限于包含源自以下病毒的基因组的核苷酸序列的载体:逆转录病毒;慢病毒;腺病毒;腺相关病毒;SV40型病毒;多瘤病毒;Epstein-Barr病毒;乳头状瘤病毒;疱疹病毒;痘苗病毒;脊髓灰质炎病毒。可以容易地使用未指出但本领域已知的其他载体。
本文所述的方法包括将细胞群(例如,体细胞群)重编程为分化程度较低的状态。如本文所用,重编程是指改变或逆转可以是部分分化或终末分化的细胞(例如,体细胞)的分化状态的过程。重编程包括细胞分化状态的完全逆转和部分逆转。
本领域已知的用于重编程细胞的任何方法都可以用于本文所述的方法中。一般而言,重编程细胞的方法包括在改变或逆转细胞分化状态的试剂的存在下培养细胞,该试剂可被称为重编程试剂。在一些实施方案中,重编程剂是改变基因(例如,OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28)的表达的核酸。
本文所述的方法包括将细胞群(例如,形成性PSC)分化成更分化或特化的状态。可以根据已知方法诱导本发明的形成性PSC分化以获得期望的细胞类型。一般而言,用于分化细胞的方法包括在诱导分化的试剂的存在下培养细胞,该试剂可被称为分化剂。在一些实施方案中,形成性PSC可以通过在提供细胞分化的条件下在分化剂的存在下培养这样的细胞被诱导以分化为原始生殖细胞、造血干细胞、肌肉细胞、心肌细胞、肝细胞、软骨细胞、上皮细胞、泌尿道细胞。因此,本文描述的方法包括在存在至少一种分化因子的情况下培养形成性PSC。本领域已知的任何分化因子均可用于将形成性PSC分化为更分化或特化的状态。分化因子的实例包括但不限于生长因子、WNT抑制剂、TGF-β抑制剂及其组合。在一些实施方案中,生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。在一些实施方案中,WNT抑制剂是IWP2。在一些实施方案中,TGF-β抑制剂是SB431542。
II.途径激活剂
本公开内容的方面基于以下令人惊讶的发现,即干细胞可以通过激活干细胞中的FGF、TGF-β和WNT在多能性的离散形成性阶段被捕获。因此,本文提供了通过在存在至少一种FGF激活剂、至少一种TGF-β激活剂和至少一种WNT激活剂的情况下培养细胞群来产生形成性多能干细胞(PSC)的方法。
(a)FGF激活剂
FGF是一个细胞信号传导蛋白家族,其在广泛的细胞过程中发挥作用。FGF家族成员包含FGF蛋白(例如,FGF1、FGF2、FGB、FGF4、FGF5、FGF6、FGF7、FGF8、FGF9、FGF10、FGF11、FGF12、FGF13、FGF14、FGF15、FGF16、FGF17、FGF18、FGF19、FGF20、FGF21、FGF22和FGF23)和FGF受体(FGFR)蛋白(例如,FGFR1、FGFR2、FGFR3、FGFR4和FGFRL1)。FGF途径中的基因和蛋白质的序列是本领域已知的,并且可以从公开可用的数据库中获得。
任何FGF家族成员的激活剂均可用于本文所述的培养方法。在一些实施方案中,本文使用的FGF激活剂对一个FGF家族成员是特异性的,例如,对FGF或FGFR是特异性的。在一些实施方案中,FGF激活剂对两个或更多个FGF家族成员是通用的,例如,对FGF和FGFR是通用的。在一些实施方案中,本文使用的FGF激活剂对FGF2是特异性的。
如本文所用,术语“FGF激活剂”是指部分或完全增强、增加或刺激FGF蛋白的生物活性的分子。合适的FGF激活剂包括但不限于蛋白质、核酸、小分子或其组合。鉴定FGF激活剂的方法可包括将FGF与候选FGF激活剂接触并测量通常与FGF相关的一种或多种生物活性的可检测变化。
如本文所用,术语“FGF”是指具有与野生型FGF多肽相同或相似的生物活性的FGF多肽。FGF多肽可具有与野生型FGF多肽的氨基酸序列至少70%或更多(例如,至少75%、至少80%、至少85%、至少90%、至少95%、至少97%、至少99%或100%)相同的氨基酸序列,并能够触发FGF信号传导途径。
各种物种的野生型FGF序列(例如,FGF2的序列)可在万维网上从NCBI获得,包括人、小鼠和大鼠。例如,编码人FGF2的同种型的核苷酸序列可在NCBI以登录号NM_002006.4(SEQ ID NO:1)获得,其相应的氨基酸序列为登录号NP_001997.5(SEQ ID NO:2)。
FGF激活剂可以是增强与细胞中至少一个FGF家族成员(例如FGF或FGFR)相关的信号传导的任何类型的分子,例如,通过增加FGF家族成员的转录或翻译,或通过增加FGF活性,或两者。在一些实施方案中,FGF激活剂可通过与FGF受体相互作用直接起作用或通过与FGF信号传导途径的一种或多种细胞内组分相互作用间接起作用。
在一些实施方案中,本文所述的FGF激活剂可将细胞(例如,ESC或iPSC)中的FGF信号传导增加至少20%或更多,例如,30%、40%、50%、60%、70%、80%、90%、95%或以上。在存在至少一种FGF激活剂的情况下增加的FGF信号传导可通过常规方法测定,例如使用蛋白质测定法如ELISA或蛋白质印迹。
在一些实施方案中,FGF激活剂将FGF途径的活性增加到足以产生形成性PSC的水平。在一些实施方案中,FGF激活剂可用于表征或探索与多能性连续体相关的阶段和/或机制。
应当理解,FGF激活剂应该能够以足够的量进入细胞以增加FGF活性,从而产生形成性PSC。在一些实施方案中,FGF激活剂以0.1至10,000ng/ml的浓度添加至细胞培养基。在一些实施方案中,将FGF激活剂以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
在一些实施方案中,用于本文所述方法的FGF激活剂是可渗透细胞的。在一些实施方案中,可以在使用细胞培养基培养细胞之前将FGF激活剂添加到细胞培养基中。在一些实施方案中,可以在细胞培养期间将FGF激活剂添加到细胞培养基中。
在一些实施方案中,FGF激活剂是蛋白质或小分子。在一些实施方案中,FGF激活剂是具有生物活性的FGF蛋白,例如FGF2。在一些实例中,FGF蛋白(例如,FGF2蛋白)可以以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,FGF蛋白以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,将FGF蛋白以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
用于本文所述方法的任何蛋白质可分离自天然存在的来源(例如,天然产生蛋白质的哺乳动物细胞),使用重组表达技术在真核或原核细胞中产生,或化学合成。可以使用本领域已知的方法以纯化形式制备可溶的、具有生物活性的FGF蛋白。
在一些实施方案中,FGF激活剂是小分子,例如有机小分子,其通常具有小于5,000kDa的分子量。合适的小分子包括与FGF的一个或多个家族成员(例如,FGF和/或FGFR)或其片段结合的那些,并且是本领域已知的或通过诸如筛选大型化合物库的方法鉴定的。
(b)TGF-β激活剂
TGF-β是属于转化生长因子超家族的多功能细胞因子,包括TGF-β(例如,TGF-β1、TGF-β2和TGF-β3)、激活素(例如,激活素A、激活素B和激活素C)、骨形态发生蛋白(BMP)和TGF-β受体(TGFR)(例如I型、II型和III型受体)。TGF-β途径中的基因和蛋白质的序列是本领域已知的,并且可以从公开可用的数据库中获得。
任何TGF-β家族成员的激活剂均可用于本文所述的培养方法。在一些实施方案中,本文使用的TGF-β激活剂对一个TGF-β家族成员是特异性的,例如,对TGF-β或激活素(例如,TGF-β2或激活素A)是特异性的。在一些实施方案中,TGF-β激活剂对两个或更多个TGF-β家族成员是通用的,例如,对TGF-β和激活素(例如,TGF-β2或激活素A)是通用的。
如本文所用,术语“TGF-β激活剂”是指部分或完全增强、增加或刺激TGF-β蛋白的生物活性的分子。合适的TGF-β激活剂包括但不限于蛋白质、核酸、小分子或其组合。鉴定TGF-β激活剂的方法可包括将TGF-β与候选TGF-β激活剂接触并测量通常与TGF-β相关的一种或多种生物活性的可检测变化。
如本文所用,术语“TGF-β”是指与野生型TGF-β多肽具有相同或相似生物活性的TGF-β多肽。TGF-β多肽可以具有与野生型TGF-β多肽至少70%或更多(例如,至少75%、至少80%、至少85%、至少90%、至少95%、至少97%、至少99%或100%)相同的氨基酸序列,并且能够触发TGF-β信号传导途径。
各种物种(包括人、小鼠和大鼠)的野生型TGF-β序列(例如,TGF-β1、TGF-β2或TGF-β3的序列)可在万维网上从NCBI获得。例如,编码人TGF-β2同种型的核苷酸序列可在NCBI以登录号NM_001024847.2(SEQ ID NO:3)获得,其相应的氨基酸序列为登录号NP_001020018.1(SEQ ID NO:4)。
如本文所用,术语“激活素”是指与野生型激活素多肽具有相同或相似生物活性的激活素多肽。激活素多肽可具有与野生型激活素多肽至少70%或更多(例如,至少75%、至少80%、至少85%、至少90%、至少95%、至少97%、至少99%或100%)相同的氨基酸序列,并且能够触发TGF-β信号传导途径。
各种物种(包括人、小鼠和大鼠)的野生型激活素序列(例如,激活素A、激活素B和激活素C的序列)可在万维网上从NCBI获得。例如,编码人激活素A同种型的核苷酸序列可在NCBI以登录号NM_002192.3(SEQ ID NO:5)获得,其相应的氨基酸序列为登录号NP_002183.1(SEQ ID NO:6)。
TGF-β激活剂可以是增强细胞中与至少一个TGF-β家族成员(例如,TGF-β、激活素、BMP或FGFR)相关的信号传导的任何类型的分子,例如,通过增加TGF-β家族成员的转录或翻译,或通过增加TGF-β活性,或两者。在一些实施方案中,TGF-β激活剂可通过与TGF-β受体相互作用直接起作用或通过与TGF-β信号传导途径的一种或多种细胞内组分相互作用间接起作用。
在一些实施方案中,本文所述的TGF-β激活剂可将细胞(例如,ESC或iPSC)中的TGF-β信号传导增加至少20%或更多,例如,30%、40%、50%、60%、70%、80%、90%、95%或以上。在存在至少一种TGF-β激活剂的情况下增加的TGF-β信号传导可以通过常规方法确定,例如使用蛋白质测定法例如ELISA或蛋白质印迹。
在一些实施方案中,TGF-β激活剂将TGF-β途径的活性增加至足以产生形成性PSC的水平。在一些实施方案中,TGF-β激活剂可用于表征或探索与多能性连续体相关的阶段和/或机制。
应当理解,TGF-β激活剂应该能够以足够的量进入细胞以增加TGF-β活性,从而产生形成性PSC。在一些实施方案中,TGF-β激活剂以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,将TGF-β激活剂以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
在一些实施方案中,用于本文所述方法的TGF-β激活剂是可渗透细胞的。在一些实施方案中,可以在使用细胞培养基培养细胞之前将TGF-β激活剂添加到细胞培养基中。在一些实施方案中,TGF-β激活剂可在细胞培养期间添加到细胞培养基中。
在一些实施方案中,TGF-β激活剂是蛋白质或小分子。在一些实施方案中,TGF-β激活剂是具有生物活性的TGF-β蛋白,例如FGF2蛋白、激活素A蛋白、TGF-β1蛋白或其组合。在一些实例中,可以将TGF-β蛋白(例如FGF2蛋白、激活素A蛋白、TGF-β1蛋白或其组合)以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,将TGF-β激活剂以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
用于本文所述方法的任何蛋白质可分离自天然存在的来源(例如,天然产生蛋白质的哺乳动物细胞),使用重组表达技术在真核或原核细胞中产生,或化学合成。可以使用本领域已知的方法以纯化形式制备可溶的、具有生物活性的TGF-β蛋白。
在一些实施方案中,TGF-β激活剂是小分子,例如有机小分子,其通常具有小于5,000kDa的分子量。合适的小分子包括与TGF-β的一个或多个家族成员或其片段结合的那些,并且是本领域已知的或通过诸如筛选大型化合物库的方法鉴定的。
(c)WNT激活剂
WNT是一个分泌蛋白家族,其对广泛的发育和生理过程很重要。WNT家族成员包括WNT1、WNT2、WNT2b(也被称为WNT13)、WNT3、WNT3a、WNT4、WNT5a、WNT5b、WNT6、WNT7a、WNT7b、WNT8a、WNT8b、WNT9a、WNT9b、WNT10a、WNT10b、WNT11和WNT16。WNT途径中的基因和蛋白质序列在本领域中是已知的并且可以从公开可用的数据库中获得。
任何WNT家族成员的激活剂均可用于本文所述的培养方法。在一些实施方案中,本文使用的WNT激活剂对一个WNT家族成员是特异性的,例如,对WNT1、WNT2、WNT3或WNT3a是特异性的。在一些实施方案中,WNT激活剂对两个或更多个WNT家族成员是通用的,例如,对WNT3和WNT3a是通用的。在一些实施方案中,本文使用的WNT激活剂对WNT3a是特异性的。
如本文所用,术语“WNT激活剂”是指部分或完全增强、增加或刺激WNT蛋白的生物活性的分子。合适的WNT激活剂包括但不限于蛋白质、核酸、小分子或其组合。用于鉴定WNT激活剂的方法可包括使WNT与候选WNT激活剂接触并测量通常与WNT相关的一种或多种生物活性的可检测变化。
如本文所用,术语“WNT”是指与野生型WNT多肽具有相同或相似生物活性的WNT多肽。WNT多肽可以具有与野生型WNT多肽至少70%或更多(例如,至少75%、至少80%、至少85%、至少90%、至少95%、至少97%、至少99%或100%)相同的氨基酸序列,并且能够触发WNT信号传导途径。
各种物种(包括人、小鼠和大鼠)的野生型WNT序列(例如,WNT1、WNT2、WNT3或WNT3a的序列)可在万维网上从NCBI获得。例如,编码人WNT3a同种型的核苷酸序列可在NCBI以登录号NM_033131.3(SEQ ID NO:7)获得,其相应的氨基酸序列为登录号NP_149122.1(SEQ IDNO:8)。
WNT激活剂可以是增强与细胞中至少一个WNT家族成员(例如,WNT1、WNT2、WNT3或WNT3a)相关的信号传导的任何类型的分子,例如,通过增加WNT的转录或翻译家庭成员,或通过增加WNT活动,或两者。在一些实施方案中,WNT激活剂可以通过与WNT受体相互作用直接起作用,或通过与WNT信号传导途径的一种或多种细胞内组分(例如β-连环蛋白,作用于β-连环蛋白的激酶或磷酸酶,与β-连环蛋白组装的转录因子)相互作用间接起作用。
在一些实施方案中,本文所述的WNT激活剂可使细胞(例如,ESC或iPSC)中的WNT信号传导增加至少20%或更多,例如,30%、40%、50%、60%、70%、80%、90%、95%或以上。在存在至少一种WNT激活剂的情况下增加的WNT信号传导可通过常规方法确定,例如,使用蛋白质测定如ELISA或蛋白质印迹。
在一些实施方案中,WNT激活剂将WNT途径的活性增加到足以产生形成性PSC的水平。在一些实施方案中,WNT激活剂可用于表征或探索与多能性连续体相关的阶段和/或机制。
应当理解,WNT激活剂应该能够以足够的量进入细胞以增加WNT活性,从而产生形成性PSC。在一些实施方案中,WNT激活剂以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,将WNT激活剂以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
在一些实施方案中,用于本文所述方法的WNT激活剂是可渗透细胞的。在一些实施方案中,可以在使用细胞培养基培养细胞之前将WNT激活剂添加到细胞培养基中。在一些实施方案中,可以在细胞培养期间将WNT激活剂添加到细胞培养基中。
在一些实施方案中,WNT激活剂是蛋白质或小分子。在一些实施方案中,WNT激活剂是具有生物活性的WNT蛋白,例如WNT3a蛋白。在一些实例中,可以将WNT蛋白(例如,WNT3a蛋白)以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,WNT蛋白以0.1至10,000ng/ml的浓度添加到细胞培养基中。在一些实施方案中,将WNT蛋白以1至10,000ng/ml、10至10,000ng/ml、100至10,000ng/ml、1,000至10,000ng/ml、5,000至10,000ng/ml、0.1至5,000ng/ml、1至5,000ng/ml、10至5,000ng/ml、1,000至5,000ng/ml或2,500至5,000ng/ml的浓度添加到细胞培养基中。
用于本文所述方法的任何蛋白质可分离自天然存在的来源(例如,天然产生蛋白质的哺乳动物细胞),使用重组表达技术在真核或原核细胞中产生,或化学合成。可以使用本领域已知的方法以纯化形式制备可溶的、具有生物活性的WNT蛋白。
在一些实施方案中,WNT激活剂是小分子,例如有机小分子,其通常具有小于5,000kDa的分子量。合适的小分子包括与WNT的一个或多个家族成员(例如,WNT1、WNT2、WNT3和/或WNT3a)或其片段结合的那些,并且是本领域已知的或通过诸如筛选化合物的大型文库的方法鉴定的那些。
在一些实施方案中,WNT激活剂是糖原合酶激酶3(GSK3)抑制剂。GSK3是一种丝氨酸/苏氨酸激酶,其已被鉴定为葡萄糖代谢的调节剂。如本文所用,“GSK3”是指GSK3的一种或两种同种型(GSK3α和GSK3β)。抑制这些同种型中的一种或两种的抑制剂是有用的。在一些实施方案中,GSK3抑制剂特异性抑制GSK3并且基本上不抑制大多数其他哺乳动物激酶。
任何GSK3抑制剂均可用于本文所述的方法中。示例性GSK3抑制剂包括但不限于BIO、AR-A014418、SB216763、SB-415286、CHIR98014(CT98014)、CHIR98023(CT98023)、CHIR99021(CT99021)和CHIR99021三盐酸盐。
应当理解,GSK3抑制剂应该能够以足够的量进入细胞以抑制其中的GSK3,从而产生形成性PSC。在一些实施方案中,GSK3抑制剂以至少等于GSK3抑制剂的IC50的浓度添加到细胞培养基中。在一些实施方案中,将GSK3抑制剂以GSK3抑制剂IC50的0.5至50倍的浓度添加到细胞培养基中。
在一些实施方案中,将GSK3抑制剂(例如,CHIR99021)以0.1至100μM的浓度添加到细胞培养基中。在一些实施方案中,将GSK3抑制剂(例如CHIR99021)以0.1至90μM、0.1至80μM、0.1至70μM、0.1至60μM、0.1至50μM、0.1至40μM、0.1至30μM、0.1至20μM、0.1至10μM、0.1至1μM和0.1至0.5μM的浓度添加到细胞培养基中。在一些实施方案中,将GSK3抑制剂(例如,CHIR99021)以0.5至100μM、1至100μM、10至100μM、20至100μM、30至100μM、40至100μM、50至100μM、60至100μM、70至100μM、80至100μM和90至100μM的浓度添加到细胞培养基中。
III.包含形成性多能干细胞(PSC)的体外培养系统
本公开内容的方面提供了包含形成性多能干细胞(PSC)的体外培养系统,其可以通过也在本文中描述的任何方法制备。
在本文所述的体外培养系统中,任何比例的细胞都可以处于多能性的形成性阶段。在一些实施方案中,体外培养系统包含至少10%或更多的形成性PSC,包括例如至少约20%、至少约30%、至少约40%、至少约50%、至少约60%、至少约70%、至少约80%、至少约90%或更多的形成性PSC。
在一些实施方案中,本文提供的体外培养系统可包含一种或多种本文所述的激活剂,例如成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂。
在一些实施方案中,本文提供的体外培养系统可包含一种或多种额外的组分,例如饲养细胞和/或支架。本领域已知的任何饲养细胞和/或支架可用于本文所述的方法和/或体外培养系统。
IV.应用
涉及如本文所述的形成性多能干细胞(PSC)的任何方法和/或体外培养系统可用于产生任何类型的细胞。例如,如本文所述产生的形成性PSC可被诱导以分化为原始生殖细胞、造血干细胞、肌肉细胞、心肌细胞、肝细胞、软骨细胞、上皮细胞和泌尿道细胞。
如本文所述的涉及形成性PSC的任何方法和/或体外培养系统可用于非临床目的,例如,用于研究目的。在一些实施方案中,本文所述的方法和/或体外培养系统可用于研究干细胞的行为(例如,发现涉及干细胞多能性的新生物学途径或过程)。
在一些实施方案中,涉及如本文所述的形成性PSC的方法和/或体外培养系统可用于确定候选分子(例如,化合物)是否能够改变体外培养系统中形成性PSC的多能性阶段。例如,可以将候选分子添加到本文所述的体外培养系统中。在合适的条件下培养合适的时间后,可以将培养系统中细胞的多能性阶段与不含候选分子的对照培养系统进行比较。如果与不存在候选分子的情况相比,在存在候选分子的情况下多能性的阶段发生改变,则表明候选分子可能改变多能性。
V.用于产生形成性多能干细胞(PSC)的试剂盒
本公开内容还提供了用于产生本文所述的形成性PSC(例如胚胎干细胞(ESC)或诱导多能干细胞(iPSC))的试剂盒。此类试剂盒可包括一个或多个容器,其包含本文所述的一种或多种激活剂,例如成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂,以及任选地,细胞群(例如,生殖细胞群或体细胞群)。本文所述的试剂盒还可包含适合于产生iPSC的重编程剂。本文所述的试剂盒还可包含适合于培养细胞群的细胞培养基。
在一些实施方案中,试剂盒可包含根据本文所述的任何方法使用的说明。所包含的说明可包括在包含如本文所述的FGF途径激活剂、TGF-β途径激活剂和WNT途径激活剂的培养基中培养细胞群的描述。该试剂盒可以进一步包括获得细胞群的描述,例如,获得包含通过自然交配、体外受精(IVF)、胞浆内单精子注射(ICSI)和体细胞核移植(SCNT)产生的囊胚的细胞群。在其他实施方案中,说明可以包括在至少一种分化因子的存在下培养形成性PSC从而产生分化细胞例如原始生殖细胞、心肌细胞或神经元的描述。
与本文描述的途径激活剂的使用有关的说明通常包括关于剂量的信息,以及用于形成性PSC(例如,ESC或iPSC)的预期生产的给药时间表。容器可以是单位剂量、散装包装(例如,多剂量包装)或亚单位剂量。本发明的试剂盒中提供的说明通常是标签或包装插页上的书面说明(例如,试剂盒中包含的一张纸),但机器可读的说明(例如,存储在磁盘或光存储盘上的说明)也是可接受的。
本发明的试剂盒处于合适的包装中。合适的包装包括但不限于小瓶、瓶子、广口瓶、软包装(例如,密封的Mylar或塑料袋)等。试剂盒可以具有无菌接入端口(例如,容器可以是具有可被皮下注射针刺穿的塞子的小瓶)。
试剂盒可以任选地提供额外的成分,例如缓冲液和解释信息。通常,试剂盒包括容器和在容器上或与容器相关联的标签或包装插页。在一些实施方案中,本发明提供包含上述试剂盒的内容物的制品。
无需赘述,相信本领域的技术人员基于上述描述能够充分利用本发明。因此,以下具体实施方案仅被解释为说明性的,而不以任何方式限制本公开内容的其余部分。为了本文引用的目的或主题,本文引用的所有出版物均通过引用并入。
VI.一般技术
除非另有说明,否则本发明的实施将采用分子生物学(包括重组技术)、微生物学、细胞生物学、生物化学和免疫学的常规技术,这些都在本领域的技术范围内。这些技术在文献中有完整的解释,例如,Molecular Cloning:A Laboratory Manual,第二版(Sambrook,et al.,1989)Cold Spring Harbor Press;Oligonucleotide Synthesis(M.J.Gait编辑,1984);Methods in Molecular Biology,Humana Press;Cell Biology:A LaboratoryNotebook(J.E.Cellis编辑,1998)Academic Press;Animal Cell Culture(R.I.Freshney编辑,1987);Introduction to Cell and Tissue Culture(J.P.Mather andP.E.Roberts,1998)Plenum Press;Cell and Tissue Culture:Laboratory Procedures(A.Doyle,J.B.Griffiths,and D.G.Newell,eds.,1993-8)J.Wiley and Sons;Methods inEnzymology(Academic Press,Inc.);Handbook of Experimental Immunology(D.M.Weirand C.C.Blackwell,eds.);Gene Transfer Vectors for Mammalian Cells(J.M.Millerand M.P.Calos,eds.,1987);Current Protocols in Molecular Biology(F.M.Ausubel,et al.,eds.,1987);PCR:The Polymerase Chain Reaction,(Mullis,et al.,eds.,1994);Current Protocols in Immunology(J.E.Coligan et al.,eds.,1991);ShortProtocols in Molecular Biology(Wiley and Sons,1999);Immunobiology(C.A.Janewayand P.Travers,1997);Antibodies(P.Finch,1997);Antibodies:a practical approach(D.Catty.编辑,IRL Press,1988-1989);Monoclonal antibodies:a practical approach(P.Shepherd and C.Dean,eds.,Oxford University Press,2000);Using antibodies:alaboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and J.D.Capra,eds.,Harwood AcademicPublishers,1995)。
实施例
为了可以更充分地理解所描述的发明,给出以下实施例。本申请中描述的实施例用于说明本文提供的方法和组合物,并且不应以任何方式解释为限制其范围。
实施例1.从小鼠囊胚从头衍生中间体PSC
包含FGF2、激活素A和GSK3抑制剂(CHIR99021)的培养条件之前被用于通过幼稚ESC的转化和体细胞重编程来生成中间体PSC(FAC-PSC)(Tsukiyama and Ohinata,PLoSONE,9,e953292014)。FAC-PSC是否可以直接衍生自小鼠胚胎仍然未知。因此,测试了植入后外胚层的从头衍生。来自E5.25、E5.5和E6.25胚胎的外胚层被手动分离并在FAC培养基中在有丝分裂失活的小鼠胚胎成纤维细胞(MEF)上培养。大多数外胚层附着于MEF,但在传代前分化或死亡(表1)。然后测试是否可以通过将整个E3.5囊胚接种到FAC培养基中的MEF上来从植入前胚胎衍生PSC。第一次传代后,虽然出现了一些PSC样集落,但大多数集落是滋养外胚层(TE)或原始内胚层(PE)来源的,这可能是由于FGF2的补充。为了抑制TE和PE细胞的增殖,我们在前6-8天将MEK抑制剂(PD0325901)添加到FAC培养物中,并在第一次传代后将其去除(图1A)。这产生了纯的PSC样集落群和稳定的细胞系(图1B和图8A)。补充高浓度的重组WNT3a蛋白(500ng/ml)可以在衍生中取代CHIR99021(图1B),但较低浓度的WNT3a(50ng/ml)导致PSC样集落的逐渐分化(数据未显示)。使用这种方法,我们可以从几个近交和远交遗传背景中以高效率衍生PSC(表1)。
表1.FTW-ESC衍生效率
*在初始传代期间观察到自发分化。
囊胚衍生的FAC-PSC表现出圆顶形ESC和扁平EpiSC的集落形态中间体(图1B和图8A)。它们在延长培养后保持稳定的生长动力学和正常核型(图1C和图8B),并且在有或没有ROCK抑制剂(Y27632)处理的情况下显示出高克隆效率(图1D)。此外,它们在转录物和蛋白质水平上表达多能性相关基因,并表现出同质性(图1E-1F和图8C)。
WNT/β-连环蛋白、FGF/Erk和TGF-β/Smad途径在从头衍生的FAC-PSC中的激活分别通过基于萤光素酶的TopFlash报告因子测定和针对磷酸化ERK和磷酸化SMAD2水平的蛋白质印迹得到证实(图8D-8E)。另一种GSK3抑制剂(SB216763)和高浓度(500ng/ml)的WNT3a可以替代CHIR99021以用于维持未分化状态,而另外两种GSK3抑制剂(BIO和CHIR98014)和较低浓度的WNT3a(50ng/ml)导致分化(图8F-8H)。此外,激活素A和TGF-β1可以互换使用(图8F和图8H)。从培养物中减去FGF2、激活素A/TGF-β1或WNT3a/CHIR99021/SB216763导致核心和/或幼稚多能性标志物的下调,或谱系和/或引发标志物的上调(图8I)。因此,需要激活FGF和TGF-β/Smad途径以及高WNT/β-连环蛋白信号传导来稳定囊胚衍生的PSC,本文称为FTW-ESC。
除了从头衍生之外,还开发了一种允许从幼稚ESC到FTW-ESC,以及从FTW-ESC到引发EpiSC的逐步和无缝过渡的方法。这是通过将培养基从2iL(2i:CHIR99021和PD0325901,以及白血病抑制因子或LIF)更改为FTW培养基和FR培养基(FGF2和IWR1,一种典型的WNT拮抗剂)来实现的(图9A)。
总而言之,这些结果证明了从小鼠囊胚中产生了中间体PSC。
实施例2.小鼠FTW-ESC处于幼稚多能性和引发多能性之间的中间状态
与幼稚ESC类似,Xist RNA FISH分析显示从头衍生的FTW-ESC在雌性细胞系中具有两条活性X染色体(XaXa)(图1G)。为了量化FTW-ESC中XaXa细胞的百分比,将X-EGFP报告因子ESC系转化为FTW-ESC,其包含整合在父系X染色体中的EGFP转基因(Bao等人,CellResearch,28,22–34,2009)。荧光激活细胞分选(FACS)分析显示超过99%的X-EGF PFTW-ESC为EGFP阳性(图1I)。接下来,将FTW-ESC转化为引发EpiSC,并检查过渡期间的X染色体失活(XCI)状态。结果显示含有Xist FISH信号的细胞的百分比从第2代(5.1%)到第4代(95.5%)显著增加(图1H和图9B),表明XCI主要发生在这一时期。此外,EGFP+细胞的百分比从第2代(89.1%)到第4代(58.9%)下降(图9C和图9D),表明XCI在过渡期间是随机的。另一方面,类似于引发EpiSC,FTW-ESC形成紧密连接(图1J),并且与幼稚ESC相比,表达更高水平的引发多能性和紧密连接相关基因(图1K和图8C)。这些结果表明小鼠FTW-ESC具有幼稚ESC和引发EpiSC的特征。
两个Oct4增强子(远端(DE)和近端(PE))分别在幼稚和引发多能状态下差异控制Oct4表达。通过培养适应将Oct4-DE-EGFP小鼠ESC系转化为FTW-ESC和EpiSC。大多数Oct4-DE-EGF PFTW-ESC为EGFP阳性,但平均EGFP信号强度低于幼稚ESC(图1L、图1M和图9E)。相反,从FTW-ESC转化的Oct4-DE-EGFP EpiSC是EGFP阴性的(图1L、图1M和图9E)。
接下来,使用两个独立的FTW-ESC系通过RNA测序(RNA-seq)进行全局转录分析,并将结果与已发表的小鼠ESC和EpiSC数据集(Bao等人,Cell Research,28,22–34,2018;Buecker等人,Cell Stem Cell,14,838–853,2014;Wu等人,Nature,521,316–321,2015)进行比较。主成分分析(PCA)显示FTW-ESC紧密聚集成一个与幼稚ESC和引发EpiSC分开的组,表明FTW-ESC获得了不同的转录组概况(图1N)。多能性特异性基因的分析(Müller等人,Nature,455,401–405,2008)证实FTW-ESC也表现出不同于ESC和EpiSC的多能性特征(图9F)。使用低输入ChIP测序(ChIP-seq)方案(Bogliotti等人,Proceedings of theNational Academy of Sciences,115,2090–2095,2018)检查组蛋白3赖氨酸4三甲基化(H3K4me3)和组蛋白3赖氨酸27三甲基化(H3K27me3)在FTW-ESC中的全局沉积,然后与已发表的ESC和EpiSC数据集(Wu等人,Nature,521,316–321,2015;P.Yang等人,Cell Systems,8,427–445.e10,2019)进行比较。数据分析表明,在FTW-ESC中,H3K4me3和H3K27me3峰在转录起始位点(TSS)周围比在ESC和EpiSC中更宽(图9G)。
总的来说,这些结果表明FTW-ESC存在于一种独特的多能性状态,推定是幼稚多能性和引发多能性之间的中间体。
实施例3.小鼠FTW-ESC共有形成性多能性的共同和不同分子特征
最近提出在体内在幼稚多能性和引发多能性阶段之间存在一个“形成性阶段”(Smith,2017)。为了检查FTW-ESC是否具有形成性多能性的特征,将FTW-ESC RNA-seq和ChIP-seq数据集与除了其他样品以外来自体内(E5.5和E6.5)和体外(EpiLC)形成性细胞的已发表数据集进行了比较(Bao等人,Cell Research,28,22–34,2018;Boroviak等人,Developmental Cell,35,366–382,2014;Boroviak等人,Nature Cell Biology,16,516–528,2015;Buecker等人,2014;Du等人,Cell Stem Cell,22,851–864,2018;Neagu等人,Nature Cell Biology,22,534–545,2020;Wu等人,Cell,168,473–486,2015;J.Yang等人,Nature,292,154,2017;P.Yang等人,Cell Systems,8,427–445,2019;Y.Yang等人,Cell,169,243–257.e25,2017)。使用RNA-seq数据集的PCA分析使FTW-ESC比E4.5和E7外胚层更接近E5-6外胚层(图2A)。一致地,FTW-ESC的全局H3K4me3和H3K27me3概况也更接近形成性EpiLC,而不是ESC或EpiSC(图2B)。还发现,与ESC相比,FTW-ESC中大多数形成性多能性相关基因被上调,而幼稚多能性相关基因被下调(图2C)(Peng等人,Nature,144,1–5,2019)。此外,选定的形成性基因的TSS周围的H3K4me3和H3K27me3信号在FTW-ESC中分别显示出比在ESC中更高和更低的水平。相反,幼稚基因的TSS周围的H3K4me3和H3K27me3水平表现出相反的趋势(图2D)。此外,通过RNA-seq分析,与ESC、EpiSC和MEF相比,FTW-ESC中鉴定了79个显著上调的转录因子和辅助因子,其在与胚胎形态发生、细胞命运决定和原胚层的形成等相关的基因本体论(GO)项中富集(图2E)。这些基因包括:Lgals9(NCBI基因ID 16859)、Zscan4f(NCBI基因ID 665902)、Zscan4c(NCBI基因ID 245109)、Taf7l(NCBI基因ID74469)、Zscan4b(NCBI基因ID 665780)、Mael(NCBI基因ID 98558)、Mef2b(NCBI基因ID17259)、Hoxa1(NCBI基因ID 15394)、Etv4(NCBI基因ID 18612)、Loxl2(NCBI基因ID94352)、Esx1(NCBI基因ID 13984)、Plek(NCBI基因ID 56193)、Irf7(NCBI基因ID 54123)、Tesc(NCBI基因ID 57816)、Zscan4d(NCBI基因ID 545913)、Olig1(NCBI基因ID 50914)、Dmrtb1(NCBI基因ID 56296)、Hnf1a(NCBI基因ID 21405)、Bhlhe40(NCBI基因ID 20893)、Msx2(NCBI基因ID 17702)、Notch4(NCBI基因ID 18132)、Tgfb1(NCBI基因ID 21803)、Stat4(NCBI基因ID 20849)、Csrnp1(NCBI基因ID 215418)、Srebf2(NCBI基因ID 20788)、Gata4(NCBI基因ID 14463)、Hcls1(NCBI基因ID 15163)、Csrnp3(NCBI基因ID 77771)、Fam83g(NCBI基因ID 69640)、Bcl6b(NCBI基因ID 12029)、Arntl(NCBI基因ID 11865)、Olig2(NCBI基因ID 50913)、Uri1(NCBI基因ID 19777)、Actn2(NCBI基因ID 11472)、Hoxa3(NCBI基因ID15400)、Zfp738(NCBI基因ID 408068)、Ankrd1(NCBI基因ID 107765)、Arid3a(NCBI基因ID13496)、Sox7(NCBI基因ID 20680)、Cebpa(NCBI基因ID 12606)、Hoxa5(NCBI基因ID15402)、Gtf2e1(NCBI基因ID 74197)、Arnt(NCBI基因ID 11863)、Skil(NCBI基因ID20482)、Cbl(NCBI基因ID 12402)、Zfp72(NCBI基因ID 238722)、Pias2(NCBI基因ID17344)、Hand1(NCBI基因ID 15110)、Prmt5(NCBI基因ID 27374)、Sap18(NCBI基因ID20220)、Eya3(NCBI基因ID 14050)、Zfp617(NCBI基因ID 170938)、Zfp866(NCBI基因ID330788)、Nelfa(NCBI基因ID 24116)、Nfx1(NCBI基因ID 74164)、Slc25a15(NCBI基因ID18408)、Zfp933(NCBI基因ID 242747)、Tfdp2(NCBI基因ID 211586)、Itch(NCBI基因ID16396)、Nkx2-9(NCBI基因ID 18094)、Zfp941(NCBI基因ID 407812)、Zfp87(NCBI基因ID170763)、Sox1(NCBI基因ID 20664)、Irf6(NCBI基因ID 54139)、Rtf1(NCBI基因ID 76246)、Dmrt3(NCBI基因ID 240590)、Recql5(NCBI基因ID 170472)、Zfp759(NCBI基因ID 268670)、E2f2(NCBI基因ID 242705)、Pura(NCBI基因ID 19290)、Txlng(NCBI基因ID 353170)、Tpr(NCBI基因ID 108989)、Hoxb2(NCBI基因ID 103889)、Irf8(NCBI基因ID 15900)、Hoxa7(NCBI基因ID 15404)、Zzz3(NCBI基因ID 108946)、Casz1(NCBI基因ID 69743)、Adnp(NCBI基因ID 11538)和Xrcc6(NCBI基因ID 14375)。
此外,通过与ESC和EpiSC比较,在FTW-ESC中还鉴定出2,783个H3K4me3-高和2,215个H3K27me3-高基因。对2,783个H3K4me3-高基因的GO分析揭示了几个项,例如,前/后模式特化和胚胎器官形态发生,其在FTW-ESC中是过度呈现的。另一方面,富含2,215个H3K27me3-高基因的GO项包括白细胞迁移和免疫系统过程的负调节等(图10A和图10B)。为了便于参考,下文列出了H3K4me3-高和H3K27me3-高基因。
小鼠FTW-ESC中的H3K4me3-高基因:DLX4、MYH11、BANF2、TNFRSF25、MKLN1、CISD3、PLEKHG3、MYOD1、DOK2、BORA、MCM7、KLC4、DUOX2、NYAP2、TRMO、IL13、KRIT1、SMIM23、BEAN1、DIAPH1、NDOR1、NUDT8、TMEM234、CRYAA、NCOA3、TMEM138、PLPP3、GIPC3、NFIC、FEZF1、ABHD14B、NMUR2、KLHDC8B、TEX37、B3GNT3、TPBGL、NXPH2、PRPF40B、RPS27A、EEF1AKMT1、USH1G、NLGN1、MEDAG、SLC25A47、KCNJ4、CBLN3、CARD19、PLVAP、ERICH6、CEP95、ASB4、COL18A1、HIRIP3、PLPPR2、SPCS2、KLHDC4、KRCC1、CFAP100、NR2E1、SLITRK1、LAMP5、RPA1、BRAP、ZAR1、GLRA2、SLC39A9、CTLA4、PARP3、RPS21、CNPY4、RPS16、ARV1、ELOVL6、RPUSD4、FSHB、TOPORS、CCDC185、RNF167、JMJD7、PAX6、POLDIP2、SHH、FES、EVX2、SUN2、ADGRL4、TTC17、PLPPR4、MORN1、GRM7、KCNK3、NXPH4、GRIK1、AIRE、HTR1F、SMCR8、COX4I1、SCUBE3、ATP2C2、REEP3、NPY5R、SPATA4、STK19、FLCN、TMEM94、MRPL13、SBDS、ATOH8、TMEM154、UBD、TLE6、TMEM43、TNFRSF11B、EHD2、ARHGEF19、PTK7、AKAIN1、GSE1、A1CF、AHSA1、PAPPA2、PSD、TFAP2A、ADAM7、AP2B1、SASS6、CBLN1、TAF4、HCST、RGS1、ASB18、CKAP2L、WFIKKN1、FBXO9、NEUROG3、ARMC6、CEBPZOS、ENO3、SLC25A32、LRRC26、SLC17A9、AAAS、OVOL1、PUS3、SLCO4C1、JARID2、ZRANB2、SYTL1、TRIAP1、TMEM198、HOXA10、KCNIP4、BRICD5、MYOZ3、RETSAT、KLHL1、NMUR1、RIDA、VSIR、MSI2、AHDC1、IL12RB2、DIAPH3、LZIC、ENOPH1、GDPGP1、TMEM263、NEK8、NOXO1、SEC61B、CYP26A1、IKZF4、ANGPT4、PKLR、GALNT6、BCL2L12、TM6SF2、SLC22A7、TMEM196、KRTAP11-1、SON、MMADHC、A1BG、SGCG、CHAD、LIG3、WDR54、ZMYND15、NEUROG1、BMT2、HPF1、SEMA4A、GPR88、CWC15、GPD1、MARK3、MPST、PROSER1、C8G、PLPPR1、TNFSF13、USP10、RXFP3、KCNN4、KLHL35、ADAM33、KCNK15、CCDC70、NSRP1、DTX3、CFAP206、NIPSNAP3A、TET1、SMAD7、NOTO、ALG3、SOGA1、B4GAT1、GRP、ATF5、IL34、LAMC3、LAMB2、ACP7、DYNLRB2、MSMB、COG4、KMT5A、GPANK1、HDAC5、NPB、IFITM5、PLPPR3、DUOX1、OXT、GP9、TTC19、MYOZ1、ARPP21、KCNG4、SREBF2、HOXC12、SYS1、ANKRD17、GPR101、NCAN、BHLHA15、SIM2、SLC2A5、PTH、CCDC191、NRN1L、CTDSPL2、NKX1-1、FGD2、TM9SF2、NR0B1、EAF1、KCNK9、LEP、VPS50、MFSD14B、PAPLN、ARSA、MFSD4A、RBM8A、LMO3、COPE、PRPH、CNTN6、DCAF17、NAALADL2、MEIOC、CTDNEP1、GGN、TFAP2D、S1PR2、ZIC1、SMC6、SPATA5、STX1B、CTNS、ARMT1、NCBP3、PRICKLE4、DES、TRADD、SNRPA、HSPA1A、PLPP2、SLC32A1、RHBG、PTGIR、RACK1、COL8A1、JHY、TNS2、ALX1、ERBB4、ACTN4、DDIAS、MIS12、KIF1C、CYP27B1、SDCBP2、ANO7、RAB27A、NECTIN1、HOXD3、ERICH4、TACR2、PLPPR5、CLMP、KCNIP1、MYH7B、CENPL、NCAM2、COPS3、LRG1、RAB35、NKX2-3、DRD1、EMG1、HPS5、SORCS3、YIPF3、IL12A、RUBCN、CRLF1、IYD、PDE6B、HOXB3、CHODL、CFAP45、MED8、WDR83、DIAPH2、BARHL1、NKX2-1、MROH6、LCT、DAND5、UNCX、INHBC、APOBR、CRELD2、MMRN1、SIRT7、HOXB1、KCNRG、SDR39U1、OLFM3、PPIL4、TMEM54、KARS、CCDC80、CRCP、OXNAD1、SRRD、ARMC5、CREB3L3、MNX1、TUBE1、MOB1A、GNA13、TMEM40、VAX1、MRPS26、LENG8、F11R、GRIA2、SNAP47、SURF2、PIPOX、PLPP4、PSMA4、IL12B、DND1、ANKUB1、ABTB1、QRFPR、NOC2L、CELSR2、DPT、APBB1IP、AUNIP、NAA50、DCUN1D5、SIX3、SLC35F6、PRMT9、CLCN4、HOXA3、MATK、LRSAM1、RNMT、RPL13、PXN、STUM、USP20、PLPP1、LRRC4C、POLH、PCP2、IMPG1、EPHA8、EREG、SLC13A4、VSIG10L、SVBP、CRACR2B、AGR3、P2RY2、FOXS1、P2RX3、EMSY、DNASE1L3、DNAAF5、ANKRD33、PTGDR、CCER1、KCNJ5、MTNR1B、GNB2、TFAP2B、PNPLA7、RIC8A、TRPC4、CRP、CILP2、NDUFS3、IDUA、ZCCHC13、TTI2、MFSD14A、SLC38A11、DLX5、QRFP、RAMP2、PTPA、PPP1R27、LINGO2、CMC4、GLRA3、MUTYH、ABHD15、MRPL14、MRPL49、TFPT、FAM91A1、HAND1、WDR46、SLC34A2、NECTIN3、KMT2B、EMILIN1、DONSON、NEPRO、ATP1A4、KRTCAP2、ZBTB32、DDX28、LMOD1、PIP4K2B、TMEM253、PTGFR、CFAP77、TRIM15、KAT7、SLITRK6、HSPG2、RBKS、GPR149、RING1、NCBP2、EFL1、KCNA5、MST1、HIC2、PRR16、HOXC10、ITGB2、PAQR6、HRH1、LY86、APPBP2、LIPE、CD151、CLEC3B、DPP10、BARX1、SHISA8、ITGB7、ARGLU1、MYL10、CDK9、ADAM18、SNAI1、PLPP7、ASPDH、DIRAS1、GABRB1、EPS8L2、MUC1、PLEKHD1、OLFM4、GSX1、STRN3、CNGA2、SIDT2、RNF40、MRPL21、WNT7B、TACR1、VIPR2、SEMA3B、RNF8、PEBP4、DBX2、DPM1、GFY、KYAT3、FAM162A、SP3、IKZF3、MRPS24、HNRNPA1、PCNX4、PON1、GRIN3B、KCTD10、TTC6、A3GALT2、OCSTAMP、LYL1、AMD1、RNASE12、GLDN、CCDC189、TNNI3、SLC22A12、DHX38、SLC6A12、RAMP3、PRLHR、GPSM3、RPL23A、PLAGL2、RHBDL1、AQP4、TNFSF9、CNTN4、SLC46A2、ART5、GABRA2、ECM1、GANC、NANOS3、CCDC137、SPRY4、CHKB、SQSTM1、ASCC1、ESRP2、SAMD11、LSM3、TRIM65、IFNK、LNP1、FCF1、GJD4、FREM3、TECRL、LRRTM4、KCNH7、SPPL2B、CHST9、OLIG2、KCNG2、TMEM200C、ZDHHC22、MGME1、NECTIN2、CCHCR1、PRPF4、GSTP1、MIR509、7530416G11RIK、OLFR1270、MIR652、VMN2R66、GM4981、PRSS44、GM6634、TAGLN、GM35206、9530082P21RIK、MIR7060、AY702102、1700022H01RIK、B230311B06RIK、PAKAP、4930415L06RIK、4930567J20RIK、GNA15、TMEM150COS、MIR124A-1HG、C230029F24RIK、VMN2R86、1700030N03RIK、4921525O09RIK、MIR5120、MIR582、CD93、SNORD92、GM37013、RPAP2、CCR7、GM5478、PRL2C1、HSF1、1700128A07RIK、GM20063、MIR6976、GDF5、SLAIN1OS、ZSCAN29、KYAT1、PCDHGB1、MIR6990、6030466F02RIK、OLFR907、GM20765、GM12128、GOSR2、4930471M09RIK、OLFR1170、GM6213、LRRC57、RBP3、KIR3DL1、VMN1R129、MRGPRA2B、DNAJB8、ZC3H12D、SLC22A26、GM21671、GM4489、E130218I03RIK、E2F8、HOTTIP、MIR181D、LAT2、1700008C04RIK、VEGFD、MEI1、F830045P16RIK、PINC、4933408J17RIK、MIR6991、ADAM26B、MIR680-2、SSXB6、SAP30BP、5730488B01RIK、4930440C22RIK、GM15517、OLFR771、OLFR1314、1700001D01RIK、GUCA1B、CCKAR、FPR-RS3、MIR193A、GM3604、POP1、DEFB41、OLFR1095、TRIM12A、RNF151、COL4A3、AI463170、RNF31、CCDC33、NLRP1C-PS、4933432G23RIK、1700110K17RIK、FBXW14、MIR5617、TIMD4、1700026J14RIK、OLFR8、HOTAIR、FNDC7、MAN1B1、PRR32、GM15679、GM12374、ZWILCH、4930544D05RIK、TCAP、NAA60、GM906、GM32511、MSR1、OLFR1344、MIR6941、RASGRP4、FBXW28、ZDHHC3、RAVER1、CTS7、SULT1C2、MIR3547、ASTX6、4932413F04RIK、MIR8100、GM17767、PLPP5、SNORA43、VMN2R92、MIR6911、MIR8103、ZFP972、FTSJ3、MIR6988、GM30173、KIF4-PS、NPCD、MIR5106、5930438M14RIK、LMNTD2、2410021H03RIK、ACNAT2、GM6567、BC048671、4930563H07RIK、AU015836、D230030E09RIK、MIR615、NCAPH2、OLFR951、1190028D05RIK、4933428G20RIK、OLFR722、MIR6350、GM5891、ELDR、OXGR1、4930557K07RIK、4933400F21RIK、GM5128、4930445N18RIK、SPATA33、MIR676、GM38426、GM19345、GM13749、DLX4OS、MRPS7、FHL5、1810041H14RIK、BC049762、FSHR、4930442J19RIK、OLFR1495、VMN1R30、2310069B03RIK、BVHT、GM16793、OLFR1166、CES4A、GM1715、DBPHT2、4930558J18RIK、SLC26A8、2300002M23RIK、TAS2R119、1700095A21RIK、ZFP944、KISS1、E230029C05RIK、GM5114、GM5113、FITM1、TULP2、GM10354、PTGER3、GM20822、OLFR344、MIR467F、5830473C10RIK、SCRG1、OLFR731、4930440I19RIK、BROX、GPS1、4930503B20RIK、2310040G24RIK、1700099I09RIK、GM14204、GM20752、1700049E17RIK2、C87414、SNORA28、PRAM1、OLFR1390、SNORA70、6430562O15RIK、LCN4、IL18R1、2010010A06RIK、PRSS43、5031425F14RIK、4930441H08RIK、SPINK4、TRIM30D、GM12159、GM32455、TESPA1、CACNG6、MIR3965、DNASE1L2、ATP6V1G2、PCDHGA6、GM13490、HOXAAS2、9330182O14RIK、GM19303、2900040C04RIK、6820426E19RIK、LINS1、4933411E08RIK、2810442N19RIK、1700024B18RIK、TMEM38A、RHNO1、4930590L20RIK、PCDHGA3、PLATR8、4930413E15RIK、GM36283、GM1527、4933412O06RIK、DAPL1、MC3R、TMPRSS11F、2810433D01RIK、MIR204、1700034K08RIK、1700036G14RIK、PCDHB5、OASL2、GM10248、GM10687、4930471G24RIK、CATSPERB、GM10710、GM4861、OPALIN、MIR465、1700027H10RIK、SLC5A2、GM20815、OLFR94、CYP2D9、RAB20、KRT222、MIR125B-2、H2-M1、DIO2、TNN、PDZD11、PCDHA5、GM3636、AKP3、SLCO6D1、BC048679、MIR5127、MIR28B、MIR6418、MIR7089、MIR706、GM4788、GM20597、GM5091、GM20172、PSMB11、GM5535、MIR3082、GM5591、VMN2R-PS11、PANTR1、SIGLEC15、PTMS、GM12238、1700022E09RIK、SERPINI2、MIR5121、P2RY10、GM5415、URAH、ERP27、MIR5104、GM10635、4930443O20RIK、ZBTB49、GPR151、SERPINB3B、GM6994、MIR7241、4933403O08RIK、H2AFB1、TBPL2、GM12695、MIR6902、GM23450、BTNL10、GM27740、1700003L19RIK、1700065L07RIK、D16ERTD519E、FBXW20、CYP4A12A、DRC7、OLFR1271、HILS1、TRPC2、OLFR1257、4930556N09RIK、LRRC10、4930431P22RIK、E230013L22RIK、MIR1892、9630028H03RIK、MIR3108、OLFR910、SERPINB9F、DNMT3L、BCL2A1B、GM536、1700007F19RIK、1700028D13RIK、SELPLG、MIR3106、GM7788、RXFP1、C1QTNF3、ZMYND10、AI606473、UBA5、ITIH5L-PS、1700009N14RIK、GM2109、4930478L05RIK、CYPT2、GM15343、GM31938、GM17597、GM4651、HAVCR1、PLATR7、SPN、PPP1R2-PS9、RNF113A1、USP5、ESP1、A930009A15RIK、4930413G21RIK、APCS、OBOX5、RBAKDN、2900092C05RIK、1700044K03RIK、2310039L15RIK、4921518K17RIK、RHOX3G、1700092C10RIK、PCDHGA9、4930548J01RIK、CPXCR1、OLFR596、ZFP280B、PRSS42、SNORD69、RP1、MIR7J、1700022A22RIK、1700095J03RIK、OLFR1507、CSTF1、GM20594、G630064G18RIK、9530020I12RIK、KLHDC7B、MIR767、1700003D09RIK、CD209B、SLC22A22、4930593A02RIK、6330415B21RIK、ARHGAP35、4930417O22RIK、NAT8F1、FSBP、PCDHA9、4930467K11RIK、MIR466Q、GM867、BYSL、ATXN7L1OS2、3110009F21RIK、ACTL9、BB031773、GM33727、1700027A15RIK、MIR326、SNHG15、1700052I22RIK、ACKR1、4932415M13RIK、G6PD2、KBTBD13、NOSIP、9130221H12RIK、GM4793、GM13315、SMIM9、MIR6420、GM3942、MIR343、8430430B14RIK、GM10440、NOS3、OLFR513、4930579F01RIK、1700040D17RIK、SPEER4C、1700009C05RIK、GM26684、AI839979、TLR9、OLFR933、H2-T3、GM4956、PLAC9B、VMN2R112、LRRC72、GM1943、CEACAM-PS1、CRYGC、4930526L06RIK、4833412C05RIK、1110002J07RIK、4930431P03RIK、UBL5、GM10471、HSD3B3、SDHD、MIR490、FYB、UPK1A、MIR671、NUDT16L1、8430436N08RIK、4933433H22RIK、4930592A05RIK、TREX1、GM15908、AMTN、AI197445、4930554G24RIK、VMN2R65、SPRTN、COX11、GM32865、MIR1298、IQCJ、GM14207、BLOC1S6OS、1700025B11RIK、SLC35G3、GM20806、GM26633、SOX6OS、GM10377、RGS18、SORBS2OS、ZFP488、MIR7088、GM15569、TCAM1、MIR3968、4930404H11RIK、CYP3A44、MIR5046、CCK、PCDHB10、1700018L02RIK、GM5640、GM17733、PRKDC、MIR692-2、MIR1966、AMY2A5、KHDC3、TREM1、D6ERTD474E、GM4301、TAS2R114、MIR3961、MIR7232、AMELX、OLFR339、GM10532、LNCPINT、OLFR553、SCGB2B12、E230016M11RIK、GM26710、GM21190、1700109G15RIK、MAGEF1、PTX3、MIR1963、GM38404、CLDN34B4、MIR28C、MIR7011、DEFB33、NTS、C330024D21RIK、CHIL5、OXCT2B、C730002L08RIK、CYP3A25、4930505N22RIK、BC042761、SPATA31D1C、MIR141、NXPE2、ZMAT5、NOL3、ADAM26A、SKINT6、GM14743、VIL1、GM11190、MYCS、GM10823、GFAP、CYP2C53-PS、GM26994、HALR1、TINAG、ZC3H11A、MIR6995、FAM166B、ENPEP、MIR3069、AI450353、BCL2L10、FBXW27、EPN3、2810408A11RIK、GM30853、SMIM22、4933427E11RIK、MIR5098、GM4750、GM10466、CLDN22、LOC102632231、4930548K13RIK、0610005C13RIK、RNF224、TNXB、OLFR924、GM17634、MIR7070、VMN1R2、6430553K19RIK、TERB1、MIR3473D、MIR448、OLFR796、MIR5118、MIR144、BCL2A1C、MIR2139、4931420L22RIK、TJP3、AU022793、MIR6395、ALMS1-PS2、GM15934、OFCC1、ATAD3AOS、4933417G07RIK、GM13547、EHBP1L1、SOD3、OSGIN1、GM35496、SNHG14、4930448I18RIK、ZFP973、GM41410、GM20219、PCDHB2、OLFR1312、VMN2R57、BSN、GM5523、4930525G20RIK、OLFR46、IL17C、TAS1R2、MIR8120、OLFR855、GRXCR1、A630023P12RIK、1700109K24RIK、GM20767、MIR7213、4932435O22RIK、1700061J23RIK、6430628N08RIK、4930432J09RIK、RNF208、1810007C17RIK、2610020C07RIK、CXCL13、VMN1R59、GUCY1B2、ACTL10、GM7714、CLEC4A2、OLFR16、GM10681、CDK11B、CYP2C38、MIOX、SNORD19、GM14496、CRCT1、MIR6973B、KRT17、TAS2R110、SNHG18、CXCL3、IFI204、MCAM、RD3、XNTRPC、1700030A11RIK、GM14486、OLFR1320、C1QA、VMN1R72、MROH3、VMN1R40、GM31763、GM14548、FCMR、MNDAL、A930012L18RIK、PADI4、4933440J02RIK、4921504A21RIK、OLFR362、1700003G18RIK、FUT7、GM36595、MIR7058、PRR30、CTRL、PCSK2OS2、GM29669、GM6194、4933400L20RIK、MIRT1、PCDHGC5、MIR7018、ZFP965、MFSD4B5、CPNE6、MIR7047、CYP2J8、PRR3、CLEC4B1、MIR6237、SNORD85、VMN1R226、MIR7029、SYCE1L、HPN、MIR1187、NPPB、MIR1192、1110015O18RIK、TMEM181C-PS、GM15694、GM12789、OLFR142、AMY2A3、KCNJ14、GM26641、VMN2R62、CD226、RNF138RT1、LRIT3、STOML3、HSFY2、9230114K14RIK、GM9961、4933401B06RIK、OLFR1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IR6373、VMN1R238、GM44505、KLRB1、PIRA2、CXCL15、6330418K02RIK、GZMA、1700113B09RIK、1700012I11RIK、SSTR4、GM10400、2310030A07RIK、ZFP967、4933413J09RIK、GM4872、YY2、OLFR298、MIR346、C8B、KRT87、4930448C13RIK、VMN1R82、TRP53、MIR5125、CHDH、VMN1R20、4930430A15RIK、MIR568、TFF3、DMRT1I、LDHAL6B、VMN1R174、ATP6V1G3、GM2516、SERPINA1D、GM20939、1700054A03RIK、GM11468、MIR7227、KRT4、SPEER9-PS1、MIR6357、SPEER2、OLFR1339、GM12018、MFAP1A、DLEU7、OLFR215、ZFP804B、PCDHB9、VMN1R38、GM33301、GM3776、MIR683-2、GM38509、2610306M01RIK、OLFR1323、MIR3090、GM8979、GM11758、GM20036、GM23363、OLFR958、PNMT、GM16104、GLOD4、GM4632、URAD、CTS3、1700049E22RIK、MIR133B、ZFP148、SPATA31、4933402C06RIK、GM15555、INSL3、GM7457、4930519K11RIK、D930016D06RIK、PCDHB13、4732414G09RIK、REG2、4833422C13RIK、4921507G05RIK、MIR6355、GM19782、4930579H20RIK、GM11681、2900079G21RIK、MUP10、1700012D16RIK、MIR143、GM30108、OLFR834、CMTM1、OLFR456、SLFN5OS、4930586N03RIK、LOC106557447、GM4251、KAP、1700092M07RIK、PI15、ABCG8、OLFR641、GM26579、GM10324、VMN1R56、MIR182、VMN2R113、4933412E12RIK、GM12130、RPH3A、GM19585、CFAP52、ACOT5、GM20268、GM23284、VMN1R139、PDZK1、5730420D15RIK、MIR3057、MAMDC4、NACAD、TTI1、GM11567、1700123J17RIK、4930558F17RIK、OBOX1、ERDR1、MIR6412、MIR3095、4930545H06RIK、4930578M01RIK、MIR130C、4930515L19RIK、ADAMTS4、GZMM、UBASH3A、PRR29、TNS4、OLFR691、OLFR322、MIR1931、MIR219A-2、MIR6368、GM1553、VMN1R184、SGF29、GM21379、9530036O11RIK、MIR9-3HG、PARD3BOS2、C330024C12RIK、MYL7、MIR1190、C030013C21RIK、GM5914、CRISP2、MIR6999、D130017N08RIK、GM15401、CLIC3、4930554H23RIK、ADAM34、NESPAS、MIR6925、PALMD、1300017J02RIK、1700012B09RIK、9430014N10RIK、GM32172、A830029E22RIK、B130024G19RIK、ARHGAP15、VMN1R23、MIR6539、TMEM175、FXYD7、ZFPL1、LOC108167416、GM6812、OLFR65、GM11217、MRGPRB3、GM8709、NDST4、4933438K21RIK、MAGEB5、MFRP、MIR6387、CYP3A16、MIR124-2HG、OLFR63、F13A1、TCTEX1D4、GM32141、GM14725、B230354K17RIK、4930474N05RIK、DEFB14、MIR3078、OLFR1269、GM10768、SCGB2B26、GM10814、4933402J15RIK、SNORD93、OLFR1135、NELL1OS、IFNA16、GM7932、4930545E07RIK、MIR6943、GM38431、R3HDM1、1810013A23RIK、CNTNAP5C、FMR1OS、1700086O06RIK、OLFR164、OLFR773、MANNR、GM29461、AI115009、GM12191、4632428C04RIK、2500002B13RIK、RSC1A1、OLFR1274-PS、MIR7091、B930018H19RIK、VMN1R121、4930428D20RIK、2210420H20RIK、OLFR1350、A730004F24RIK、ZFP27、GM2027、MIR3472、MIR7660、GM10845、MYADML2、LYG2、4933433F19RIK、SNORD1B、5430402E10RIK、TERB2、1700020D05RIK、GM7271、RPRL1、GM12925、MIR6921、GM7134、SVAL2、GM6644、4930448F12RIK、2310003N18RIK、4930515G16RIK、GM26685、GM33337、CXCR3、CETN1、MIR599、CYPT1、LOC102632463、VMN1R15、MUP9、GM28535、4933413L06RIK、CCDC183、PMFBP1、GM3336、GM15326、CYGB、MIR219B、8030451O07RIK、BC051019、6530403H02RIK、MIR5099、4930584F24RIK、YOD1、TAS2R139、4930512B01RIK、PGLYRP4、1700031L13RIK、5033428I22RIK、ALKBH4、PTGS2OS2、RNF166、ZFP750、NSMCE2、CBR2、MIR7020、CCDC146、MAU2、RAB11FIP4OS2、GM36536、DPPA2、CCDC121、EID3、GM29686、1700031A10RIK、NUP98、GM22109、1700054K19RIK、GM32693、GM29811、SCG2、F830208F22RIK、PAUPAR、4930405D11RIK、A930031H19RIK、GM26760、LYZL1、GM10486、GM21814、SNX17、1700023F02RIK、SPEER4F1、4930502E18RIK、9030612E09RIK、MIR6942、NUP62、MIR7230、4930488B22RIK、SDR16C6、MIR6398、CCDC163、OLFR183、GM11827、4930583P06RIK、GM31747、MIR147、MIR200C、GM2042、LAO1、GM15179、CCDC34OS、CES2A、OLFR332、C87198、1700125G22RIK、RBM46OS、SELENBP2、SLC44A4、1700109G14RIK、PLATR10、CDH5、PDZD3、GM15509、DIO1、MUP18、GM19276、1700111N16RIK、D430036J16RIK、MIR9-3、1700003I22RIK、GM20362、4930524C18RIK、MIR6402、1700109I08RIK、MIR7236、GM5941、GM10638、BBOX1、OLFR380、LOC105245869、AA545190、GM6345、4930568G15RIK、LTA、MIR155HG、3930402G23RIK、GM10548、SNTN、F630040K05RIK、4930404A05RIK、IP6K3、ZFP366、GM4425、MIR1899、OLFR1090、GM2012、4933427D14RIK、SPIN2-PS1、COLEC10、MUP15、MIR8099-2、MIR7023、LHX1OS、KCNJ6、SERPINA3F、GM21992、1700030M09RIK、GM38403、4930539M17RIK、4930429F24RIK、VMN2R83、1700010J16RIK、4930558G05RIK、4930529C04RIK、4921513I03RIK、GM11266、GM13848、AQP6、RNF222、OLFR1193、CEACAM14、MSGN1、4921533I20RIK、OLFR1118、LOC108168459、NRP、A330069E16RIK、MIR664、3000002C10RIK、2310010J17RIK、4930474H20RIK、2310020H05RIK、COG8、4930405L22RIK、OLFR143、NPHS1OS、F930015N05RIK、MUP21、MIR6975、AU023762、KRTAP4-16、PRSS32、IZUMO1R、B020031M17RIK、4930524B17RIK、GM25018、2510003B16RIK、OLFR156、4933430M04RIK、HAVCR2、RHOX5、CELA3A、LRRC74B、A530006G24RIK、1700016P04RIK、GM1140、PCDHGA12、RETNLA、PCDH12、GM12505、MIR9-1、GM5538、PRSS45、RINL、GM26839、GM5886、WT1OS、4930564C03RIK、4930532I03RIK、ANKRD23、PLATR4、GM30551、ZAR1L、GM11529、FTCD、GM20319、MIR3089、MIR691、2610027K06RIK、C730036E19RIK、MRGPRA4、GM5108、NUDT12OS、GM15631、SMPD5、MIR24-2、GM11482、ROBO4、ITGB6、MIR26B、1700065J11RIK、MIR3092、MUSK、PARD6A、MIR378D、2010001A14RIK、2310001H17RIK、1700123O20RIK、LIPO3、VMN2R58、MIR6968、OLFR95、4930461G14RIK、GM27162、MIR7067、GPR141、MIR6403、RFPL4B、SULT2A8、GM12633、LOXL1、1700066C05RIK、1700121L16RIK、PCNX3、MIR3058、D230017M19RIK、GM44501、A930001C03RIK、OBOX7、GM6961、MIR6354、H2-M10.4、CLDN34C4、1700061F12RIK、MIR3080、VMN2R24、CSMD3、TBX5、LBX2、4930519F24RIK、1110028F18RIK、CYPT14、MIR511、PTPRCAP、ADAD1、GM32014、IRGC1、FAM104A、GM1968、4930480K23RIK、APOA5、OLFR470、MIR1982、SNORD12、SLC6A16、JMJD8、H2-K2、1700030O20RIK、4930518P08RIK、TRIM58、PRSS21、4930548G14RIK、4930533N22RIK、GM28979、GM30539、MIR10A、OLFR197、4930539C22RIK、FHITOS、VMN2R6、SLC13A1、ZFP648、GM10684、IFI27、OLFR49、GM5177、MIR295、1700095J12RIK、GM15939、WNT1、ARHGAP15OS、OLFR294、MIR7094-2、1700027J07RIK、1810021B22RIK、TMEM217、FAM170A、RNASE13、1700101O22RIK、MRPL43、ATG7、B020004C17RIK、PAX4、4931417E11RIK、MIR1905、STPG3、4930592C13RIK、VMN1R64、PKP3、4930404N11RIK、FENDRR、4930425L21RIK、IQCB1、ADORA3、UGT1A10、GM4792、GK2、GM4432、9330178D15RIK、GM732、IL13RA2、VMN1R100、GM29678、VMN1R60、LNCPPARA、4930546C10RIK、MIRG、MIR7671、A530053G22RIK、MIR1906-1、MIR6379、VMN2R75、CCER2、GM32856、1700039M10RIK、MIR7032、GM17751、RHOX3E、SPEER1、2310001K24RIK、GM13944、4930529K09RIK、ARHGAP8、OLFR418、GM44504、ZFP408、GM12911、GM26682、BC048644、A530058N18RIK、MIR7085、MIR6348、SPACA7、AGBL4、MIR3079、MIR383、CLEC4F、MIR21B、GM36582、VMN2R13、MIR105、GM2115、LKAAEAR1、SRPR、FOXI2、HOXB6、RHBDD3、FAM181A、PCDHGB8、MIR8119、GM6559、C030018K13RIK、NIM1K、DEFB7、PRDX6B、5830428M24RIK、HSDL1、ZFP319、VMN1R27、4930474N09RIK、SNORD14C、A330008L17RIK、MIR449C、A930033H14RIK、SNORD88A、GM30400、GM11651、MIR8095、GM32921、MRGPRB8、LNCENC1、MISP、GM7072、MIR18、IK、USF3、GM36738、E030011O05RIK、4933416E03RIK、TUNAR、IQCF1、2310008N11RIK、PBLD1、A730020M07RIK、OLFR1305、IL1RAPL2、SPDEF、MIR99AHG、ADAM28、GM10375、A630072M18RIK、APOL11A、TNNC2、4930505G20RIK、FMOD、RBM12、GM20356、CFHR1、CYB561D2、SOSTDC1、GM15543、MIR181C、4930428O21RIK、TGM6、E030018B13RIK、GM12381、1700001G01RIK、4930435F18RIK、P3H3、4930542M03RIK、EVX1OS、4930444M15RIK、OLFR725、6030407O03RIK、GM4988、LRRIQ4、KLRA17、PDILT、4933421I07RIK、4930500F04RIK、MIR208B、MIR6376、GM21188、MIR686、CNR2、DLL3、GM7904、GM20257、SLC25A27、NAT8F4、4930591E09RIK、SLC34A3、SLC9C1、4930578N18RIK、KCNMB4OS1、A330093E20RIK、IL4I1、LACTBL1、TAS2R123、4930401O12RIK、BACH2OS、4930513D17RIK、AMHR2、GM25212、OLFR478、ZPLD1、ANKRD60、4930486I03RIK、CD36、LILRB4A、ZFP740、MIR3063、GM19935、METTL21C、GM41341、PDIA2、TMPRSS3、GM20110、GM8765、HOXB7、4833422M21RIK、4930527G23RIK、4930425O10RIK、LOC102634389、D030024E09RIK、AGTR2、4930453L07RIK、CST10、TTC36、LOXL4、GM17745、OLFR31、MIR6953、OLFR982、B230209E15RIK、GM29443、GM15091、QRICH2、MIR6409、DEFB48、A230107N01RIK、MIR7235、OLFR1057、GM5934、SERPINB6D、MIR21A、GM17753、GM29687、OLFR502、GM4951、4933402D24RIK、EPS8L3、OLFR340、GM44502、MIR7076、GM6760、GBP11、HORMAD1、ANKRD27、MIR3100、GM16701、ZFP966、VIT、DCST1、4930587E11RIK、VMN2R55、AANAT、SLFN9、TBXAS1、OLFR1306、LOXL3、MIR6896、FAM219AOS、OLFR952、4930434J06RIK、GM36117、2310043O21RIK、CHRNA10、KIF19A、OLFR455、A930007I19RIK、H2-M9、MIR145A、1700015F17RIK、CARLR、TCF23、GM16364、GM28590、A830035O19RIK、GM10549、5430405H02RIK、VMN1R48、VMN1R234、VMN1R91、GM12794、GM16404、TPRG、1700010K23RIK、SHBG、GM11729、GM15723、CRYAB、2410004I01RIK、GPR174、OLFR786、GM853、NRIP2、GM5795、CD209C、AMY2B、CHIL6、2810025M15RIK、PARP9、OLFR177、CELRR、GM5570、NLRP1B、GLT8D1、OLFR566、HSD3B5、PVT1、GM6614、4930579D09RIK、CKM、1110028F11RIK、E330016L19RIK、MIR6537、KHDC1B、MIR6927、MIR1191B、ZSCAN10、3110039M20RIK、A330076C08RIK、GM20745、VMN1R89、LGI1、GM4832、MIR6344、KLRA2、GM20125、1700108F19RIK、1700100I10RIK、DKK4、OLFR279、GM5524、GM14405、MIR137、MIR6346、GM28626、COX7A1、VMN2R114、GM9871、TBC1D22BOS、4932414N04RIK、MIR6899、GM38670、GM12339、HOXB5、GM10754、OLFR987、4930555B12RIK、GM10665、RNU11、1700001F09RIK和9330104G04RIK。
小鼠FTW-ESC中的H3K27me3-高基因:MYH11、BANF2、LAYN、IER5L、CACNA1A、TRMO、OPRL1、SMIM23、CIITA、PTK6、LRCH1、SBSPON、IQSEC3、CRYAA、CD34、CCKAR、CYP1A1、CMYA5、CCR6、DPEP2、PTX4、PYGB、NRARP、DACT3、FN3K、SSPO、KHSRP、B3GNT3、NKAIN1、PHLDA2、TPBGL、TNNT2、TTC8、CHIC2、ZAN、KCNA6、SLC22A18、ETNPPL、SMAD6、SH2D7、KLHL26、CARD19、CTTN、GBF1、MCM5、KISS1、SUN5、CALB2、SLC4A1、MARK4、CPT2、ADGRL1、SPPL2C、KLK15、SLC34A1、CFAP100、SLITRK1、SPATA3、ZAR1、PSMB1、CACNB1、MESP2、NPBWR1、VPS37D、SDS、SAYSD1、MC3R、CD247、FBXO39、CST7、ADGRG3、SNPH、MAF、ANO1、BNIP1、BTC、TOX2、KRTDAP、CCDC185、TNNI1、FOXL1、NOL4L、CCND1、SUN2、ARID3B、DCAKD、NUP210、SNX20、CD19、PLPPR4、SSTR3、GRM7、KCNK3、SMC1B、CENPE、SYCP2、EPHB6、PEMT、KCNA3、KLHDC7B、PPT1、DCC、RAC2、TSN、KBTBD13、TMED9、SRC、SPARC、KDF1、ENTPD6、SLC2A10、TTLL1、AKAIN1、KCNA10、RIMS2、ADAMTSL4、FGF20、PLD4、CYTH2、EXOC3、SHE、ZFP37、BTNL2、CFAP74、UBE3C、CMTR2、PSMG3、SDE2、SMTNL1、CEMIP、TEX29、SLC29A2、PTGDR2、KCNIP4、PTPN20、MYOZ3、VOPP1、ZNRF4、BAMBI、DENND2D、ADGRE5、NMUR1、NMRK2、VSIR、COL9A3、GRXCR1、VWF、EXOSC3、MIOX、BOLL、DGCR2、KRT74、INPP5J、NPDC1、ANGPT4、RD3、DUSP22、ARC、FCMR、TMEM196、RAD54L2、FUT7、GRAMD4、MB、CHMP6、A1BG、RASAL1、SGCG、LYPD5、SEMA4A、SLC30A4、SFTPD、PDCD1、SVOP、EMP2、PLPPR1、RAPGEF1、CD48、ADAR、KLHL35、ASTL、RETN、CCDC70、TMPRSS9、TOLLIP、MLXIPL、HAS3、AKT3、FCRLB、PRKAB2、MED15、OSBPL5、SIX5、NXNL1、LRRC71、DYRK1B、CHGA、SLC46A1、ATF5、CHAC1、STAM2、DHRS3、NOD2、TRPV1、SRXN1、GLRA1、ACP7、DYNLRB2、ACBD3、FDXR、GRIN3A、PGLYRP2、IFNE、CCDC86、PLPPR3、C5AR2、KCNG4、CTSF、HSD17B12、GNG12、ADAMTS15、POU3F1、PSCA、MDH1B、C2CD2、NKX1-1、HAS1、SULF2、TTYH1、FKBP6、IL18、SLC10A4、NRF1、LEP、MFSD4A、UCP1、TMEM141、SLC18A2、TBC1D16、MEIOC、TXNDC16、PCSK9、CDKN1C、TNFRSF14、FCHO1、PTGDS、RABAC1、ZNHIT3、KRT82、PROM2、PDZRN3、SBK2、PDIK1L、HSPA12A、ANKRD35、ADGRG1、ADAMTS10、TEX36、SLC2A4、LARS2、RBM15、NECTIN1、SLC8A2、ERICH4、NAGPA、VWCE、PLPPR5、CEP72、KCNIP1、NCAM2、C1QB、KDM8、GPR176、DRD1、PISD、TRIT1、PFN3、LPL、SORCS3、RNF169、TMEM92、HERPUD1、PDE6B、KCP、BRF1、MOB2、CSNK1D、MIB1、PDGFB、ERN2、HPD、SLC25A41、PDZD7、RTKN、B2M、ACR、NEK6、ZHX2、FADS6、CHURC1、KLF10、SLFN14、GABRA4、AGBL1、FAM162B、NUP93、PSMC4、ACBD6、COL4A4、ILVBL、POP4、GOLIM4、PDE1B、ATP6V1B2、TRH、ADGRG5、AKAP5、NFKBIE、PRODH2、KRT4、JAM3、GPR61、CACHD1、SBK3、PLPP4、ERAP1、IL12B、RARRES2、PRKAG3、CFAP58、SYT5、DENND1A、QSOX2、EPHX1、CLP1、ARHGEF10L、EIF4E1B、HSD17B2、MPP2、STUM、FAM166A、TPCN2、TM9SF4、DMRTA1、CLPTM1L、HEMGN、EXOSC6、ACER1、TMEM176B、INCA1、WAC、VSIG10L、ARL5C、CELF5、TNS1、IL15RA、TRIM10、DPEP1、EXOSC9、HERC1、ANKRD33、TBCD、UBE2T、CCDC183、MTNR1B、CD300LG、PGLYRP4、PRR5L、RAB40B、ALKBH5、STAP2、ARL2、IGLON5、DISP2、ERICH5、CCL24、CDH16、TMC7、JAK3、LMTK3、LIN28A、CDH5、NR0B2、LTA、CCDC130、OTOS、LRRC27、RAB11FIP1、PSMB7、MAP2K3、HILPDA、LMOD1、CFAP77、SPATA32、FAM204A、CYP4X1、KIF12、GPR149、KCNA5、MST1、TTC4、LRP3、PRR16、NEU4、UPK2、CCDC174、PTH1R、MYT1、LY86、TROAP、NINL、TRPM5、ARMC1、SPNS3、CHRNB4、KDM2A、MEF2D、MEIS3、SHISA8、SIN3B、FOSB、XKR6、MYL10、USP31、PLPP7、ASPDH、TBX5、KLC2、AQP8、SERTAD4、TH、KCNF1、EPS8L2、OLFM4、CASC4、BAIAP2L2、ENDOV、UPK3A、MOGAT1、SLAMF8、TPM4、STRBP、RUFY4、FAM221B、CRB2、PRICKLE2、TMEM176A、ARTN、GPRC5A、CTBP1、WDR61、GPR45、DHCR7、LZTS1、SPTLC3、PEBP4、KCNQ1、LKAAEAR1、NXT1、ALDH1L1、TMEM9、GIMAP8、TTC6、TACC2、PACS2、ELMO2、GLDN、SEMA4B、FBLIM1、COL20A1、CNR2、MCOLN2、SLC22A12、INSR、POLG、PELI3、PPP1R1A、TNFRSF13B、AQP4、SSC5D、CYB5R4、CDKN1B、NDE1、SLC16A8、SLC46A2、DAO、LPAR5、PCK1、YES1、FXYD6、SULT2B1、NLRC5、SAMD11、TBATA、TNFRSF18、PHF12、NUB1、FREM3、IL12RB1、HAGH、NWD1、LYPD4、CNDP1、PCMTD2、KCNG2、TMEM200C、RNH1、H13、MIR6980、CRLF2、4930524O08RIK、GM4981、GMFB、TTL、COX19、TLN2、TFCP2、AY702102、ADAMTS6、EEF2KMT、TMEM150COS、MIR124A-1HG、DDI2、MIR5120、SUMO1、GM37013、GM7550、DHRS1、ZFP638、MIR6976、TVP23A、SLC26A7、FHL2、ZCCHC7、CTNNA3、6030466F02RIK、IL13、GM20765、CLPB、3110045C21RIK、2610203C22RIK、IRAK3、CYC1、4930471M09RIK、RBP3、APBB1、ZFP422、GM21671、HOTTIP、SCG3、CHCHD3、4930505K14RIK、IPO11、ARID1A、MC2R、F830045P16RIK、ZFP12、MIR6991、ZXDC、RIPK3、RHOG、MIR3107、SMYD5、PLPP3、CHCHD6、TXNDC9、TBC1D12、MIR193A、TRIM68、SCAMP2、NDUFS4、MIR874、MRPL35、PTPRN、IPP、COL4A3、GPR84、TRP53BP1、E330017L17RIK、9530077C05RIK、ZFP354B、MKRN2、TIMD4、CYP4B1、CD209F、SUCLG1、JUNB、H2-DMB1、UBE2J2、4933438B17RIK、ALG10B、ZFP30、GM32511、GM13283、TEX37、OLFR12、CSTAD、NSMCE4A、1700030C10RIK、PLA2G3、2510039O18RIK、ANGEL1、GM17767、CRH、PRMT6、GM30173、OLFR1419、FOXJ2、NPCD、AI661453、FIBIN、DCPP3、RTCA、SNRPB2、CAMSAP2、TAC1、MOS、OSM、TEKT4、CLK3、BC048671、4930563H07RIK、MIR615、GM6034、MPZ、RANBP2、TNPO3、OXGR1、FXYD2、4930445N18RIK、ZBTB46、EYA3、MEDAG、POM121、PPT2、GM38426、TPTE、ANKRD42、PTPN2、DLX4OS、RNASET2B、SIAE、YBX3、NES、GM21119、UBL4B、GM16596、GM19689、CBLN3、CES4A、GM1715、PCDHB6、5031434O11RIK、ERC1、1700095A21RIK、CDK5RAP3、ZFP322A、ACER3、ERICH6、GULP1、AFG3L1、4930440I19RIK、4930503B20RIK、KRT16、SPCS2、CWH43、GM7102、SPP1、LCN4、CXXC5、PCDHGB4、UGP2、5031425F14RIK、SPINK4、TRIM30D、APLP2、ZZEF1、NHLRC4、GM32455、CD74、H2-Q9、PPM1G、PCDHGA6、HOXAAS2、9330182O14RIK、YPEL1、STAMBPL1、2900040C04RIK、CTLA4、PRDM9、TSC1、TTC39A、DERA、PCDHGA3、ZFP59、4930413E15RIK、4933412O06RIK、DAPL1、SETD2、G2E3、2700054A10RIK、RAD18、H2-D1、CTU1、4930520O04RIK、PCDHB5、NUS1、CCL22、TMUB1、GM10687、CREBL2、GM10710、TAPT1、RPGRIP1、BHMT、ZFP329、IGFBP2、POLD4、TLDC2、ZFP961、AGRP、INO80、PCDHA5、AKP3、KRT14、PINX1、MIR5127、MIR6769B、SNTG1、CD300A、ALMS1、NUDT15、FAHD2A、CMTM3、PRR23A2、PSMB11、CLCN1、RESP18、PAIP2B、PANTR1、SIGLEC15、1700022E09RIK、AU041133、ABHD16B、YLPM1、ERP27、MIR5104、MIR152、INPP5F、MATN2、MIR7241、FCRL6、TSPYL4、GM23450、SLC7A6、4930402H24RIK、USP8、BTNL10、GSTT3、AHSG、CYP4A12A、GM14023、ADGRL4、GM16582、HILS1、TRPC2、4930556N09RIK、MICALL1、TMED3、E230013L22RIK、KLK4、LIN7C、FOXN1、TRAK1、MIA2、ZSCAN18、SEC61A1、TTC14、MIR3108、GM1987、RFTN2、GM536、RNF213、TRAF7、PRDM4、GM7788、PARL、MIR6944、GM2109、BPIFC、SLC2A9、6530402F18RIK、PCDHB19、A430033K04RIK、H2-M3、9230112D13RIK、CCDC175、EPB42、OBOX5、SAXO2、RBAKDN、SMC2OS、KLRA1、1700044K03RIK、DPP3、TEX30、GM15421、PCDHGA9、E130018O15RIK、SLURP2、PUM3、1700095J03RIK、CCDC102A、SLC30A8、4930558C23RIK、CD209B、ACOT12、6330415B21RIK、PCDHA9、HPGD、CHMP1B、LOC100861615、3110082I17RIK、PPP6C、ATXN7L1OS2、B230208H11RIK、KIDINS220、ACTL9、OLFR521、GM33727、1810026B05RIK、ZFP105、ACKR1、TMEM210、2310015A10RIK、MPP4、SMIM17、A130077B15RIK、9530080O11RIK、GM4793、MIR6420、FFAR2、GM3942、TBC1D19、1700063D05RIK、8430430B14RIK、4930579F01RIK、1700040D17RIK、NRBP1、CNN3、1700009C05RIK、GM26684、TFPI、ZFP787、AI839979、TLR9、MRVI1、EXPH5、H2-T3、GM4956、SSH2、5430421F17RIK、DUSP13、TLCD2、GM1943、CEACAM-PS1、4833412C05RIK、4930431P03RIK、GM10471、4930483O08RIK、AADAT、MIR6416、NR1D1、FYB、MIR671、MRPL9、IL17RC、4933433H22RIK、ZFP133-PS、GM12669、EID1、GM15908、PAPPA2、A330048O09RIK、A230051N06RIK、HEPACAM2、GRN、BLOC1S6OS、ANKRD13C、GM26633、DDX50、PBX4、GM10377、C030005K06RIK、MT4、MAP7D1、4921509C19RIK、SH2B2、ARHGAP39、ZFP51、GM15569、CD209G、MIR3968、4930404H11RIK、MIR5046、PCDHB10、FBXO3、ZFP26、4933430N04RIK、GM17733、MIR692-2、STRIP1、BFSP2、SHMT1、DCT、VEZF1、GM10532、LNCPINT、GM21190、C4B、1700109G15RIK、ASB18、MAGEF1、GM15501、MIR1963、GM38404、RNF145、COX6A1、STX18、ARMC6、GK5、MIR7011、1700034G24RIK、NAB2、GSDMA2、MSANTD2、STKLD1、FNTB、GM5577、ZFP109、FAM45A、KLHDC1、KLHL31、MORN5、SAP130、ZFP950、ZFP541、HALR1、2900041M22RIK、GAL3ST3、EIF2AK4、PCYOX1、CLCN7、2210404E10RIK、4930483J18RIK、MIR3069、AP1G2、MRGPRF、CES1A、GM10466、TLK2、ZFP768、GM17634、TERB1、MIR5118、BCL2A1C、SPX、RAB3D、MIR2139、CCDC42、MIR6395、RHEB、OFCC1、RIDA、GM13547、SOD3、TWF1、NSUN5、DGUOK、MPO、PREX2、TEX261、DUPD1、GM20219、PCDHB2、ZFP235、APOL7A、VMN2R57、SERPINC1、COG1、SDHAF3、4930426L09RIK、GM5523、ZFP688、TAS1R2、MIR8120、A630023P12RIK、GM20767、MIR7213、GGA2、6430628N08RIK、HSD3B2、MAT2A、ZFP964、GM9833、4930432J09RIK、GPR85、ACTL10、CLEC4A2、GM11978、UNC119、RAB2A、2310002F09RIK、PLA2G4D、LYPD2、9030624G23RIK、CRCT1、MIR6973B、FBXL19、ZFP746、CXCL3、ALDH3A2、PKLR、SPR、KLHL21、ITGAL、AP3S1、ZFP512、GM14486、SENP7、ASMT、NARS2、FSTL1、TM6SF2、UBOX5、TOM1L2、ZFP947、ZFP212、TMCC1、BTBD7、ULK2、GM6639、4921504A21RIK、OLFR463、PRR30、PCSK2OS2、4933400L20RIK、ZFP110、MIRT1、FSD2、ZFP612、MFSD4B5、CPNE6、MIR7047、PDXK、IRS2、CCL21B、LMAN2L、FASTKD1、NCK2、SYCE1L、HUNK、NOMO1、ANKAR、TMEM181C-PS、CYP4F18、MTMR3、GM16677、FGG、SP7、HPF1、ABCA6、SREK1、4930478P22RIK、FCER2A、PCDHB12、PCDHGC4、PLEK、CYP4F40、PRND、CLEC1A、CACUL1、ZFP131、SKINT10、NAP1L5、MPST、LRIF1、HRC、MFSD4B1、ZFP239、ZFP511、LRRC3C、CELF6、SNX31、TBKBP1、GM5111、RSPH1、LSM8、PCDHGA7、OLFR545、DNAJC5B、SMCO3、PCDHB22、UBE2V2、TIGD5、MIR142、PCDHGA5、4930557F10RIK、PCDHGB7、PSMD5、IFI47、CES2B、5033406O09RIK、GPX6、MIR205、GPR19、MIR7214、4930523C07RIK、TOMM20、PABPN1L、GM14057、1700020N18RIK、MIR7000、CFAP206、9130204L05RIK、ECI3、PCDHGB5、MSI1、SPAG17、TCL1B2、GIMAP1、B4GALT1、PPP1R2-PS3、GCFC2、PRSS2、TLR12、GM30731、4631405J19RIK、GM3002、PCX、GM16617、NKAPL、4930558K02RIK、RBM34、DNAJA4、DNAJB6、MIR7K、A430005L14RIK、4930511A02RIK、IGFN1、ADCK2、COPZ2、ZFP583、GM9731、SPDYE4B、PLATR22、SPRN、SMIM13、PTF1AOS、OTUD4、SEC61G、NKIRAS2、WDR17、4933422A05RIK、OGDH、CD1D2、1700006H21RIK、MIR6906、GM10639、GM15972、DTNB、PCDHGB2、CFI、CTSL、PSMD14、RAD21L、MED4、1700073E17RIK、SSBP1、9330198I05RIK、CALU、OPTN、GM6712、GM9530、PCGF6、ZFP707、GM38438、4930506C21RIK、C530044C16RIK、OLFR750、RDH9、PXMP4、MIR6239、PCDHB21、TGM4、LCE1M、HERC3、PEX11A、KLHL22、4933432I09RIK、OLFR449、5430431A17RIK、UBXN10、MIR592、4930550C17RIK、TOMM70A、TAC2、GZME、ZKSCAN4、OAZ3、ERGIC2、PHGR1、9530052E02RIK、TMCO5、FCGR1、SLC36A1、BAG3、PALLD、1700125H20RIK、GM29684、RBM6、ZFP572、MIR7021、ZFP266、APOBEC4、PGAM1、4930519G04RIK、RABL2、3300002I08RIK、ACSS2、RPS27L、GSTT4、ARHGEF18、PLCXD2、2610206C17RIK、ITGAE、GNGT2、1110036E04RIK、MIR6362、、DR1、PANTR2、HPDL、EAR10、1700016C15RIK、CALHM1、ACBD5、CRIP3、FST、1110038F14RIK、FUT4-PS1、4921536K21RIK、CYB5D2、GM15997、ACAD9、CLDN7、HSDL2、ACVR2A、HTT、IRS3、FUT2、TAOK1、1700066J03RIK、PON2、TLR2、4930524B15RIK、SEC11A、VTN、HSF5、9430078K24RIK、OLFR1368、MIR6358、TUBG2、1810044D09RIK、PCDHGA2、PBP2、PTPRV、BTG2、MLLT10、GJA10、AW011738、NEUROD6、MIR3083、GM13446、H2-Q6、GM5105、H19、MIR6378、GALNTL6、RPL17、GM6083、4930522O17RIK、PCDHB17、FADS2、ARHGAP27OS3、GM5424、CHRNE、PCDHB18、DTX4、4921529L05RIK、CAR14、ACTR3B、LMO3、CCIN、GM4559、9330175E14RIK、A230009B12RIK、ZRANB1、TRAF6、CRY2、HOXB5OS、6030471H07RIK、NAALADL2、ZDHHC13、FBXL12OS、SLC15A5、GM3363、1700020M21RIK、TGM5、MYCBP、IL17RE、UPK3BL、MIR7216、2610316D01RIK、ODF3B、FEZ1、HMGCLL1、CYP4F14、DPPA3、ACTL11、GM36246、D030068K23RIK、ARIH1、GP5、5430434I15RIK、ISOC2B、C430042M11RIK、HFE、DMPK、1700064M15RIK、1700001G17RIK、C2CD4D、AW549542、1700016K19RIK、GM16675、WDR1、3300005D01RIK、ACACA、MAPKAPK5、RDX、PRICKLE4、F2R、GM4285、SIRPA、DDX18、PLPP2、PCDHA10、NCKAP1、PCDHGA11、PIGG、GM8633、TMEM266、ATP9B、ELOVL5、RACK1、MTMR9、MIR6974、H3F3A、ZFP931、GM10584、GM13238、MAPK12、RSPH9、JHY、RCN2、ZMAT3、ALKBH3OS1、PCDHGC3、LNCBATE1、GM26689、HMGN1、GLRX2、KRTAP5-4、ALG8、GM5868、CPE、BC003965、MRLN、KCNIP3、OTUD6B、GAL3ST4、GM17619、BGLAP、PCDHB20、ORC6、FASL、CCDC166、S100A5、TNFRSF1A、MTPN、GPM6A、ZFAND6、3300002P13RIK、GM9999、A430078G23RIK、SPATS2L、DHX8、CHIL1、H2-T-PS、4933406G16RIK、TRPM1、POLN、MIR7225、MRGPRD、2200002J24RIK、MIR6367、FGFBP3、CCDC92B、1700029F12RIK、BC147527、TTC39AOS1、1700094M24RIK、ITPRIPL1、LRRC61、MIR8090、FLRT2、KNSTRN、ERCC6L2、GM26688、ANKRD36、MALL、TRIM42、GZMK、ACSBG1、NAGLU、ZFP791、KRT2、MRGPRE、ATP5K、GM38414、KBTBD2、CLSPN、CAPZA3、ACTL6A、SMU1、IQCK、GM15825、PCDHGA10、4930447F24RIK、C1QTNF4、ACTG2、SLC25A10、D3ERTD751E、TOMM7、SLC22A21、GM29683、MFSD4B4、PPA1、MAST2、PELI1、A730006G06RIK、GSDMC4、1700001C02RIK、SPINT5、ZFP467、MIR7221、MIR6923、4931408C20RIK、PCDHGB6、RNF32、VWA3A、EEA1、PCDHB16、LAMTOR4、ZFP62、COL28A1、MIR8110、LRRC25、COQ6、BORCS6、HBA-X、ESRRA、RIOK2、TBL2、TMEM235、ZFAND5、PCDHGA4、NR1D2、C030029H02RIK、U2AF1、VWC2L、ZFP759、GM5142、PPIG、MIR6240、HERC2、LCE1D、MIR1953、9430091E24RIK、LRRIQ1、GPX3、RCE1、CCR9、HBQ1A、PCDHB7、YY1、MIR146、GTF2F2、LOXL2、TMEM120A、GM5294、TEKT5、ZKSCAN1、ZFP433、LOC100862268、SPOPL、CPNE4、MIR466F-4、CCDC91、KCNQ1OT1、ELOF1、GM16630、4933406C10RIK、1700017L05RIK、PCDHB4、MIR149、2310011J03RIK、HCRTR2、DCLK2、MGAT4C、MIR145B、STK25、4932438A13RIK、L3MBTL4、MMP2、RAD52、B3GNT6、MIR7215、MED31、ZFP760、GZMA、1700113B09RIK、KIF3B、SSTR4、SLC35B1、SYNB、AP1M2、HCAR1、SLC24A1、KRT87、DNAL4、ZFP704、ZFP128、DNAJC13、MIR568、TFF3、DMRT1I、RABGGTA、GM11468、BBS5、SPEER9-PS1、SYCP1、GM5122、1700113H08RIK、SHPK、RLN3、ATF7、ADAM29、OLFR215、PCDHB9、THUMPD3、EDRF1、LY6G6C、PPP1R32、AMH、GM38509、D6ERTD527E、FAM90A1B、MIR3090、D5ERTD579E、BTNL9、GM23363、MSH5、PNMT、TSGA13、1700049E22RIK、BC002163、TMEM74、4933402C06RIK、PUM2、GM7457、4930519K11RIK、PCDHB13、4732414G09RIK、NDN、GM6588、FGF6、MRPL48、MRO、SLC13A2OS、TSNAX、GM11681、MIR143、CMTM1、NCEH1、ABHD8、DUSP2、SLFN5OS、4930586N03RIK、DNAJC10、ZFP286、TRIML1、ACYP2、CDNF、ACOT5、GM20268、GRIP1OS2、MIR3085、LAP3、SHF、BTG3、CNGB1、FBXW10、ERDR1、4921504E06RIK、NHEJ1、MIR5103、SMIM14、ATP5G2、ADAMTS4、SPTLC1、PRR29、ITPR1、CD3G、MIR219A-2、SLC35F6、OIT1、UBE2M、FGF15、TTC30A2、MIR9-3HG、MCOLN1、GPX7、PPIE、TMA16、C030013C21RIK、WFDC3、ATP6V0E、4930554H23RIK、MIR6925、PALMD、1700012B09RIK、AU021092、9430014N10RIK、A830029E22RIK、EXO1、ARHGAP15、GCM2、LHPP、RBM46、CLDN12、TEX12、SLC25A24、SIMC1、OLFR65、4930565D16RIK、CHID1、4933438K21RIK、CFAP20、AGAP3、MIR124-2HG、SMPD2、OLFR63、GM32141、PCP2、SNRNP25、GM10768、CPA5、PRSS29、DPH1、TTC1、TFF2、TRIM16、4930579K19RIK、1700086O06RIK、CSTL1、ADAMTS13、NR1I3、CCDC182、DECR1、CYB5A、GM19434、CCDC184、ANKLE1、1700061I17RIK、POLR2B、MIR135A-1、DYRK4、8430437L04RIK、RSPH6A、CLDND2、1810024B03RIK、ACOT1、ZGLP1、LYG2、ZFP2、NUCB2、IQCF5、FFAR3、GM7271、HK2、TAF11、RTTN、GM14124、HDAC10、MIR6921、9330179D12RIK、EMSY、GM6644、RAB23、4930515G16RIK、PSMB4、KLF13、HEXDC、FAM183B、EZR、4933407E24RIK、DNASE1L3、PCDHA12、CCER1、FYTTD1、SLFN8、LPAR3、ERI3、PDSS1、GM3336、A730018C14RIK、GM15326、8030451O07RIK、6530403H02RIK、MIR5099、TUG1、PDXK-PS、ZFP747、TM2D1、PKNOX2、5033428I22RIK、CD1D1、SLC4A5、KLK11、BOLA1、KDELR2、TRP53I11、RTCB、CBR2、CCDC121、HIST4H4、MIR7B、A730013G03RIK、GM22109、FAM71F2、IDUA、GM29811、SCG2、GM15441、F830208F22RIK、PAUPAR、A930031H19RIK、4632415L05RIK、SUMF1、RCBTB1、KTN1、GM13003、EQTN、GM3317、FBXL8、ARL8B、GM14424、GM31747、MIR10B、PCK2、PRDX1、SACS、S100A3、BBS4、ACTR3、CR2、GM3264、AI504432、ESYT2、PAK1、CES2A、ISM2、OLFR332、C87198、RPL5、EXOC5、9630028B13RIK、SELENBP2、AVL9、DIO1、NTPCR、4930524C18RIK、CD200、D830013O20RIK、COPS4、FAM186A、LOC105245869、IRGM1、AA545190、TMEM115、MIR804、MIR155HG、PRSS34、F630040K05RIK、SH2D2A、ITGA5、IP6K3、A230050P20RIK、ZFP366、GM4425、EPHX3、CD300C2、4933427D14RIK、MED6、HCLS1、SERPINA3F、POC5、1700030M09RIK、1700012D14RIK、NEPRO、4930539M17RIK、AHCYL1、4933402J07RIK、GM13031、AKAP10、H2-Q7、4921513I03RIK、DHRS7B、IGF2BP2、GM13848、NVL、TREH、PCDHA3、OLA1、UBB、DARS、TM4SF4、AMOTL2、MICU3、MIR6405、RORC、1700037H04RIK、4930487D11RIK、4930405L22RIK、1700030F04RIK、UEVLD、GM11346、LZTFL1、SLC25A13、AU023762、ZFP637、DBR1、SLC25A31、ILDR1、GM25018、6820408C15RIK、DYNLL2、OLFR156、RHOX5、4933431E20RIK、GPRIN3、DYNLT1B、CELA3A、VMN2R9、LRRC74B、A430090L17RIK、PCDHGA12、AI987944、TRP53RKA、GPR89、GSDMA3、MIR598、GM26839、PRSS22、GSTM1、FAR2、RIMKLB、PLATR4、ZFP101、GM11529、CLASP1、MIR1903、COQ10B、CRYGB、CLEC3B、ZFP939、5830454E08RIK、ZFP41、GM15631、1700060C20RIK、PKMYT1、ITGB6、ZSCAN12、C030037D09RIK、ACY3、CAR5A、UFM1、PCDHB11、MIR378D、1700123O20RIK、DKK3、ZFP445、4930461G14RIK、EPDR1、NBAS、MIR7219、RIIAD1、A530010L16RIK、PCDHA11、1110059G10RIK、BPIFB1、GKAP1、HSPA12B、PCF11、RMND5A、PACRGL、H2-M10.4、MIR3080、COG2、PSME2B、NOP58、JPX、ADAD1、METTL7A2、IRGC1、VPS45、4930480K23RIK、APOA5、SLC22A5、GABRB1、MIR208A、MIR1982、SNORD12、2610005L07RIK、SLC6A16、S100A6、S100A14、TRIM58、4930451I11RIK、4930548G14RIK、GM28979、HMOX2、CD276、YWHAE、GM14317、SLC13A1、ZFP648、POGK、PDE6G、OLFR49、VPS13B、GAP43、4921531C22RIK、1700027J07RIK、MIR1895、1810021B22RIK、ZFP386、GM5796、AP1G1、ZFP879、B020004C17RIK、TMEM170、KRT78、4931417E11RIK、4933430I17RIK、HBA-A1、4930592C13RIK、MS4A15、OLFR726、POGZ、SELENOF、MIR8092、4930425L21RIK、SLC36A2、LLGL1、STAT6、MIR670、SCGB3A1、SH2D4A、GM29678、TRAM2、LIPT2、IGDCC3、LNCPPARA、NDEL1、4930546C10RIK、CD4、GM15050、GLCCI1、GM6313、WBSCR25、CCER2、COG6、MIR7032、SEMA3B、1700072O05RIK、2310001K24RIK、GM13944、NR2C2、UBE2H、GM26682、MIR6348、SPACA7、TJAP1、GFY、MIR3079、KYAT3、MROH7、AQP7、CUEDC1、FAM13B、ATG16L1、TRAF1、MIR21B、GM36582、ZC3H8、RNF19A、PPIH、DIS3L2、FOXI2、RNF187、PTCHD3、PCDHGB8、FKBP9、GM6559、BDKRB1、P2RX1、DEFB7、BLOC1S2、INIP、4930474N09RIK、ARPIN、ADAM6A、A330008L17RIK、GM11651、MIR8095、GM32921、UBE2W、TNFRSF23、AU040320、ITPRIPL2、HP、GGT7、TUNAR、IQCF1、GIPC1、CCDC106、2310008N11RIK、PBLD1、MIR690、A730020M07RIK、H2-Q5、5930430L01RIK、CCDC85A、MFSD1、FBXL20、CYSRT1、PTS、4930505G20RIK、FMOD、CLASP2、MXD1、CYP17A1、RNF24、TDRKH、SOSTDC1、GM15543、E030018B13RIK、TSPAN3、4930435F18RIK、4930542M03RIK、EVX1OS、DNMT3B、CYP4F41-PS、TRIML2、ZFA-PS、CAPN3、SYNPO2L、SLC4A10、DUXBL1、NGDN、MANSC1、MIR208B、GM21188、ZFP442、MFSD7A、CEACAM15、EMC7、NOVA2、KCNMB4OS1、GRIA4、FBXO46、HSPA1B、ACAP3、2900097C17RIK、ANKRD60、MIR7086、UCKL1OS、GM19935、METTL21C、DDX27、TNFRSF10B、KLK9、TRIM17、TRPM7、4930425O10RIK、CCDC142、TRHR2、4930453L07RIK、ABI1、B3GALT6、1700017G19RIK、TCERG1、SLC25A2、GPATCH4、GM5779、MED9OS、TPSAB1、MIR7235、RPN1、TMC5、4930553P18RIK、GM17753、GABRA2、DYNC1I2、EPS8L3、PCDHA1、SPATA31D1D、C1RA、NPM3-PS1、GTDC1、COL11A1、VIT、CHKB、TBXAS1、6820431F20RIK、FAM219AOS、4930434J06RIK、2310043O21RIK、RLF、A930007I19RIK、CARLR、SUOX、COA3、FIGNL2、PHLPP1、SHISA4、LTBR、2610507I01RIK、RHBDD1、GM10636、SHBG、2410004I01RIK、ESCO1、PMIS2、GM5087、AGO1、LRRC40、MRPL46、CD209C、PTPRJ、GYG、CELRR、CYP2D10、4933417O13RIK、PAPSS1、4930579D09RIK、SNORD83B、SIGLECG、WDR7、MIR6537、KHDC1B、PPIL6、MIR1191B、PCNX2、FKBP5、PM20D1、9130019P16RIK、NAF1、TICAM2、ELMOD2、ZFP454、GM4832、KLRA2、EVA1B、OLFR279、PCDHB3、CXCL2、MIR137、MIR6346、THRSP、UTS2、PTPMT1、1810013L24RIK、RAB6A、1700110I01RIK、4932414N04RIK、MIR6899、TAF7、LIX1L、GM12339、MIR7066、GM10575、DYNLT1F和LTA4H。
据推测,形成性多能性与低线粒体呼吸有关(Smith,Development,144,365–373,2017)。本文描述的研究发现,与ESC相比,FTW-ESC中大多数线粒体复合物COX基因和三羧酸循环酶被下调,并且参与糖酵解的酶被上调,表明FTW-ESC更多地依赖于糖酵解而不是线粒体呼吸(图10C)。形成性多能性的另一个预测特征是部分上皮化(Smith,Development,144,365–373,2017)。通过在3D Matrigel中在自我更新条件下培养ESC、FTW-ESC和EpiSC来检查ESC、FTW-ESC和EpiSC的上皮化状态,并监测玫瑰花结和管腔形成(Shahbazi等人,Nature,122,881,2017)。结果表明,FTW-ESC可以有效地形成类玫瑰花结结构,但形成管腔的能力有限(图2F和2G)。
尽管在转录组水平上相似,但FTW-ESC和EpiLC确实表现出不同的特征。大多数幼稚多能性相关基因在FTW-ESC中的表达水平高于EpiLC(图10D)。另一方面,形成性多能性基因的子集(例如,Fgf5、Otx2、Pou3f1、Hes6和Pim2)在FTW-ESC中的表达水平低于EpiLC(图10D)。H3K4me3和/或H3K27me3水平与差异基因表达模式一致(图10E)。还进行了使用针对几种多能性相关基因的抗体的蛋白质印迹。OCT4蛋白水平在FTW-ESC和EpiLC之间具有可比性。然而,与EpiLC相反,NANOG以高水平表达并且在FTW-ESC中几乎检测不到OTX2(图10F)。
总之,我们的结果表明小鼠FTW-ESC具有形成性多能性的几个分子和细胞特征。
实施例4.小鼠FTW-ESC表现出嵌合体和PGC双重能力
为了测试FTW-ESC是否具有嵌合体能力,将EGFP标记的FTW-ESC注射到E3.5囊胚中,然后将胚胎移植到代孕雌性中。FTW-ESC对不同的胎儿组织有广泛贡献,并表达来自所有三个胚层的谱系特异性标志物(图3A和图11A以及表2A-2B)。成年毛色嵌合体也通过将C57BL/6FTW-ESC注射到近交白化B6或远交ICR囊胚中产生(图3B和表2A-2B)。通过将源自相同遗传背景(C57BL/6)、相同性别(雄性)和相同传代(P5)的相同数量的PSC(12个细胞)注射到E3.5白化B6囊胚,将FTW-ESC的嵌合体形成效率与幼稚ESC进行比较。FTW-ESC生成毛色嵌合体的效率低于ESC(FTW-ESC的14/25或56%,相对ESC的13/16或81.25%)(图3C和表2A-2B)。为了确定FTW-ESC是否对种系有贡献,检查了Oct4-DE-EGF PFTW-ESC对E13.5性腺中胎儿生殖细胞的贡献。发现10个性腺中有6个含有EGFP+信号(图11B)。此外,将C57BL/6FTW-ESC衍生的嵌合体与WT白化B6小鼠杂交,观察到有效的种系传递(图3D和表2A-2B)。总而言之,这些结果表明FTW-ESC可以促成能够进行种系传递的嵌合体。
表2A:小鼠FTW-ESC的嵌合体结果的总结-胎儿嵌合体结果
表2B:小鼠FTW-ESC的嵌合体结果的总结-成体嵌合体结果。
与ESC和EpiSC不同,形成性EpiLC对通过BMP处理的PGC-LC诱导有反应,其然后在体内或体外进一步分化后形成功能性配子。为了评估FTW-ESC的PGC能力,通过培养适应将双Blimp1-mVenus(BV)/Stella-ECFP(SC)报告因子ESC系转化为FTW-ESC。使用为EpiLC开发的3D聚集诱导方案,FTW-ESC被成功分化为BV+/SC+细胞(图11C)。接下来通过化学抑制研究了FTW-ESC诱导PGC-LC期间不同信号传导途径(FGF、TGFβ、WNT和LIF)的作用。有趣的是,添加FGF受体(FGFR)抑制剂(PD173074)显著增加了BV+/SC+群体(图3E、图3F和图11D)。另一方面,WNT或LIF途径的抑制略微降低PGC-LC(BV+/SC+)诱导效率(图11D)。FGFR抑制也促进了基于分选SSEA1+/CD61+群体的从囊胚衍生的FTW-ESC的PGC-LC诱导(图11E)。与未诱导的FTW-ESC(第0天)和BV-/SC-细胞相比,在PGC-LC诱导期间从第2、4和6天分离的BV+/SC+细胞显示PGC标志物的显著上调(图3G)。免疫荧光(IF)分析证实PGC标志物TFAP2C和BLIMP1在第6天的PGC-LC中在蛋白质水平上共表达(图3H)。此外,还评估了诱导的PGC-LC的表观遗传状态。IF分析表明,与非PGC-LC(BLIMP1-或TFAP2C-细胞)相比,第6天PGC-LC(BLIMP1+或TFAP2C+细胞)中5mC和H3K9me2水平降低,H3K27me3水平升高(图3I-3K)。
总的来说,我们的结果表明,除了嵌合体能力外,FTW-ESC还适用于体外直接PGC特化。因此,FTW-ESC被指定为嵌合体(希腊语为)和PGC双能多能干细胞,或XPSC)。
实施例5.FTW条件支持稳定马ESC和无转基因iPSC的衍生
接下来测试FTW培养物从目前缺乏稳定ESC的物种中衍生PSC。在FTW条件下,ESC成功地衍生自通过胞浆内单精子注射(ICSI)和体细胞核移植(SCNT)产生的马囊胚(被称为马FTW-ESC,或FTW-eqESC)(图4A,图4B,图12A和表1)。不需要MEK抑制剂PD0325901,在最初3天内补充10%胎牛血清(FBS)有利于FTW-eqESC衍生。FTW培养物还通过使用编码人SOX2、KLF4、L-MYC、LIN28、OCT4和TP53 shRNA的组合的附加型质粒载体转染马胚胎成纤维细胞(EEF)来支持马iPSC(FTW-eqiPSC)的产生(图4A、图4C和图12B)。两个独立的FTW-eqiPSC系在不同传代(P5、P10、P15和P20)时的转基因状态通过检查以下来评估:1)人重编程因子的表达(图4D);2)来自共转染的pCXLE-EGFP附加型载体的EGFP表达(图12C);和3)每个细胞的附加型载体的总拷贝数(图12D)。发现在长期传代(P20)后,两个FTW-eqiPSC系都获得了无转基因状态,倍增时间和细胞周期概况的变化可忽略不计(图12E和图12F)。
FTW-eqPSC可以维持在MEF上或无饲养层条件下(Matrigel,MG)(图4B和图4C),在转录物和蛋白质水平上表达多能性基因(图4E、图4F和图12G),并表现出碱性磷酸酶活性(图4G)。FTW-eqPSC可以在多次冷冻/解冻循环后有效恢复,在长期培养后保持稳定的生长动力学(图4H)和正常(n=64)二倍体染色体数目(图12H)。类似于小鼠XPSC,FTW-eqPSC可以在无ROCK抑制剂处理的情况下以克隆密度传代(图4I)。
实施例6.FTW-eqPSC表现出多能性的分子和功能特征
对FTW-eqESC、FTW-eqiPSC、EEF、马内细胞团(eq-ICM)和滋养外胚层(eq-TE)进行了RNA-seq。无监督层次聚类和相关性(UHC)分析表明,与EEF和eq-TE相比,FTW-eqESC和FTW-eqiPSC与eq-ICM更紧密地聚类(图4J)。EEF转录组与FTW-eqESC、FTW-eqiPSC和eq-ICM的转录组的成对比较鉴定了eqESC、FTW-eqiPSC和eq-ICM中的1,798个普遍上调的基因(图12I)。GO分析显示许多富集的项与细胞分裂和增殖相关,例如DNA复制起始、染色体分离和细胞分裂(图12J)。还进行了ChIP-seq分析,发现FTW-eqESC和FTW-eqiPSC显示出相似的全局H3K4me3和H3K27me3概况(图12K)。分析揭示了在与基因表达相关的几种多能性相关转录因子(例如SOX2、KLF4、NANOG和POU5F1)的启动子区域内增加的H3K4me3标记和降低的H3K27me3水平(图4K)。
为了在功能上评估FTW-eqPSC的多能性,进行了体外(胚状体)和体内(畸胎瘤)分化测定。IF和组织学分析表明FTW-eqPSC分化为来自所有三种胚系的细胞和组织:外胚层、中胚层和内胚层(图4L和图4M)。还通过定向分化从FTW-eqiPSC产生了跳动的心肌细胞(图12L和图12M)和神经元(图12N和图12O),表明它们对诱导信号有反应并且能够进行多谱系定型。
一个针对多能性的更严格的测试是嵌合体形成,其测量供体PSC在被引入植入前宿主胚胎后是否可以广泛定殖所有胚层组织。由于在马中进行此类实验的逻辑困难,首先检查了FTW-eqPSC整合到囊胚的ICM中的能力。单体Kusabira-Orange(mKO)标记的FTW-eqiPSC被注射到马囊胚中并在体外培养两天,然后通过荧光显微镜和IF分析嵌合ICM形成。注射后两天,发现FTW-eqiPSC掺入6个注射的马囊胚中的6个(100%)的ICM中,并表达多能转录因子SOX2(图5A和表3A-3C)。还检查了在注射囊胚或桑葚胚后,mKO标记的FTW-eqiPSC向小鼠、绵羊、山羊和猪囊胚的种间ICM掺入。一致地,FTW-eqiPSC有效掺入宿主ICM并表达OCT4(小鼠)和SOX2(绵羊和猪)(图5B、图13A和表3A-3C)。接下来,通过按照既定方案将注射了FTW-eqPSC的小鼠囊胚在体外扩展培养中培养另外6天,确定FTW-eqiPSC是否能够存活并保留在小鼠植入后外胚层中。可以在小鼠外胚层内检测到FTW-eqiPSC,尽管检测率低于ICM(22.2%,6/27),并且对OCT4染色呈阳性(图12B)。
ICM和/或外胚层整合是嵌合体潜力的指标,但不是嵌合体能力的决定性证据。接下来,使用注射了EGFP标记的FTW-eqESC的小鼠囊胚进行胚胎移植。有趣的是,检测到(5/18,27.8%)E7.75和(4/24,16.7%)E9.5小鼠胚胎中的许多EGFP+细胞(图5C、图12C、图12D和表3A-3C)。在胚胎切片和使用谱系特异性标志物(外胚层,TUJ1;内胚层,FOXA2;中胚层,SMA)共染色后,发现FTW-eqESC在E9.5小鼠胚胎中分化为所有三种生殖谱系(图5D和图12E)。这些结果证明了FTW-eqESC促成小鼠多谱系嵌合体形成的能力。
总的来说,这些结果表明FTW-eqPSC表现出多能性的分子和功能特征。
表3A:马FTW-iPSC和FTW-ESC的嵌合体形成结果总结–ICM掺入
表3B:马FTW-iPSC和FTW-ESC的嵌合体形成结果总结–体外胚胎培养
表3C:马FTW-iPSC和FTW-ESC的嵌合体形成结果总结-体内胚胎移植。
实施例7.FTW-eqPSC具有形成性多能性特征
接下来,确定FTW-eqPSC是否还保留了小鼠形成性多能性特征。为此,将eq-ICM和FTW-eqPSC的转录组概况与小鼠ESC、XPSC、EpiLC和EpiSC进行比较。发现eq-ICM与小鼠ESC聚类在一起,FTW-eqPSC与小鼠XPSC和EpiLC沿着幼稚-形成性-引发轴对齐(图5E)。该分析还鉴定了1,619个小鼠引发多能性相关基因(小鼠EpiSC相对ESC中的上调基因)并检查了它们在马(eq-ICM和FTW-eqPSC)和小鼠(ESC、XPSC、EpiLC和EpiSC)样品中的表达水平。发现这些基因在FTW-eqPSC中的表达模式介于幼稚(eq-ICM和小鼠ESC)和引发(小鼠EpiSC)细胞之间,并且更类似于小鼠XPSC和EpiLC(图12F)。使用马特异性引物,通过RT-PCR分析证实了一些小鼠形成性标志物在FTW-eqPSC中的表达(图12G)。从ChIP-seq数据集中,还观察到FTW-eqPSC中形成性多能性相关基因的TSS周围H3K4me3标记的富集和降低的H3K27me3水平(图12H)。此外,FTW-eqPSC可以形成类似于小鼠XPSC的类玫瑰花结结构和紧密连接(图12I和图12J)。
还检查了FTW-eqPSC是否允许直接PGC-LC诱导。与小鼠XPSC类似,发现FTW-eqESC也可以响应BMP信号传导并产生PGC-LC,如通过以下证实的:1)表明在用BMP4诱导3天后几种PGC标志物的表达水平显著升高的qPCR分析(图5F)和2)指示几种PGC标志物(PRDM1、TFAP2C和DPPA3)也在蛋白质水平上表达的IF分析(图5G)。为了确认PGC-LC可以从FTW-eqESC直接诱导,通过在紧靠终止密码子之前T2A-EGFP序列在内源性NANOS3基因座中的CRISPR/Cas9插入生成了荧光NANOS3报告因子系(图5H和图12K)。选择一个纯合NANOS3-EGFP克隆以确认PGC-LC诱导,并在BMP4处理一天后观察EGFP信号。EGFP+细胞的数量在第2天和第3天继续增加(图5H)。还进行了FACS分析,结果发现在诱导1、2和3天后分别有6.9%、31.7%和33.2%的细胞为EGFP+(图5I)。有趣的是,与小鼠XPSC不同,使用FGFR抑制剂PD173074的处理没有增强来自FTW-eqESC的PGC-LC诱导效率(图12L)。
总之,与小鼠XPSC类似,FTW-eqPSC在体外响应于PGC特化,并可促成小鼠胚胎中的体内嵌合体形成。因此,FTW-eqPSC在下文中被称为马XPSC(eqXPSC)。
实施例8.人FTW-iPSC的生成和表征
最近,在FTW条件(FAC)下从人包皮成纤维细胞(HFF)生成了iPSC细胞系,该细胞系在E21-28猪胚胎中表现出嵌合能力(命名为FTW-hiPSC_#1)。然而,FTW-hiPSC_#1尚未得到详细表征,并且它们是否类似于在相同条件下生长的小鼠XPSC仍然未知。此处,另一个FTW-iPSC系是从具有附加型质粒载体的HFF生成的(命名为FTW-hiPSC_#2)(图6A和图6B),并进行了广泛的表征。FTW-hiPSC表达多能性标志物SOX2和OCT4(图6C)(Wu等人,2017年)。有趣的是,FTW-hiPSC对KLF17、SUSD2和CD24(公认的人幼稚(KLF17和SUSD2)和引发(CD24)多能性标志物)染色呈阴性(图6D和图6E),但均匀表达形成性多能性标志物OTX2(图6C和图6E)。与引发的hiPSC相比,FTW-hiPSC显示出稍长的倍增时间(图6F)。与引发的hiPSC不同并且类似于小鼠和马XPSC,FTW-hiPSC可以在不用ROCK抑制剂处理的情况下以克隆密度传代(图6G)。传代33次后,不再检测到附加型载体序列,证明FTW-hiPSC可以保持无转基因状态(图14A)。此外,类似于FTW-hiPSC_#1,FTW-hiPSC_#2也可以形成由来自所有三个胚系的组织组成的畸胎瘤(图14B)。
接下来进行使用两种FTW-hiPSC系的RNA-seq分析,并与幼稚和引发的hESC比较其转录组(Takashima等人,Cell,158,1254–1269,2014;Theunissen等人,Cell Stem Cell,15,471–487,2014)。3D PCA图显示FTW-hiPSC紧密聚集在一起,并且与幼稚hESC和引发hESC分开(图6H)。RNA-seq分析鉴定了在FTW-hiPSC中特异性上调的936个基因(图6I),这些基因在与区域化、前/后模式特化、胚胎器官发育等相关的GO项中富集(图6J)。
这些结果表明,与小鼠XPSC类似,FTW-hiPSC处于不同于幼稚和引发状态的多能性状态。
实施例9.FTW-hiPSC具有形成性多能性特征
接下来,将FTW-hiPSC的转录组与已发表的培养的人胚胎(F.Zhou等人,Nature,572,1–27,2019)、幼稚(重置-hESC、5/6iLA-hESC、HNES、4i-hESC、2iLI-hESC、2iLIF-hESC和NHSM-hESC)和引发的hESC(Guo等人,Stem cell Reports,6,437–446,2016;Hu等人,Science Advances,6,eaaz0298,2020;Irie等人,Cell,160,253–268,2015;Sperber等人,Nature Cell Biology,17,1523–1535,2015;Takashima等人,Cell,158,1254–1269,2014;Theunissen等人,Cell Stem Cell,15,471–487,2014)的RNA-seq数据集进行比较。PCA分析表明,幼稚hESC(重置-hESC、5/6iLA-hESC和HNES)、FTW-hiPSC和引发hESC分别聚集在更靠近人E6、E8和E10-12外胚层的位置(图7A),这指示FTW-hiPSC代表类似于形成性外胚层的中间多能状态(Smith,Development,144,365–373,2017)。此外,与幼稚hESC相比,在FTW-hiPSC中许多形成性多能性相关基因被上调并且幼稚多能性相关基因被下调(图7B)。此外,类似于小鼠和马XPSC,FTW-hiPSC也可以形成类玫瑰花结结构和紧密连接(图14C和图14D)。有趣的是,与几项最近的研究一致(Guo等人,Development,144,2748–2763,2017;Huang等人,Cell Stem Cell,15,410–415,2014;Nakamura等人,Nature,537,57–62,2016;Pastor等人,Cell Stem Cell,0,323–329,2016),在一些幼稚条件下生长的hESC的转录组(4i-hESC(Irie等人,2015),2iLI-hESC(Hu等人,Science Advances,6,eaaz0298,2020),2iLIF-hESC和NHSM-hESC(Sperber等人,Nature Cell Biology,17,1523–1535,2015))聚集在靠近E8或E8-10人外胚层之间的位置,表明它们的中间多能性状态(图7A)。
接下来,研究了FTW-hiPSC是否可以在体外直接响应BMP信号传导以形成PGC-LC。依赖两个表面标志物:EpCAM和CD49f(整合素α6)(其被显示选择性地标记人PGC-LC(Sasaki等人,2015))用于纯化PGC-LC。在用BMP4诱导期间,~17.52%(第2天)、~26.57%(第4天)和23.84%(第6天)的细胞是EpCAM/CD49f-高(图7C)。与未诱导的FTW-hiPSC(第0天)相比,EpCAM-/CD49f-高细胞显示出几种PGC标志物的显著上调(图7D)。此外,IF分析指示PGC标志物:TFAP2C、PRDM1和NANOS3也在蛋白质水平上表达(图7E)。类似于小鼠XPSC,FGFR抑制得到改善(尽管程度低于小鼠),而WNT/LIF途径抑制降低了PGC-LC诱导效率(图14E)。
综上所述,这些结果表明,与小鼠和马XPSC相似,FTW-hiPSC也表现出形成性多能性的分子和细胞特征特性,并且适用于体外直接PGC-LC诱导。基于先前证明的在早期猪胚胎中的这些以及它们的嵌合能力,FTW-hiPSC在下文中被称为人XPSC(hXPSC)。
实施例10.XPSC的跨物种转录组比较
在相同条件下生成和培养的来自多个物种的XPSC使得能够检查不受不同培养参数干扰的物种特异性多能性特征。为此,进行了马、小鼠和人XPSC的跨物种转录组学比较。UHC分析显示马XPSC与人XPSC相比小鼠XPSC更接近地聚集(图14F)。该分析鉴定了分别在人、马和小鼠XPSC中特异性表达的1,220、1,269和1,540个基因(图14G)。最丰富的物种特异性GO项包括:1)人:轴突发生和神经元投射引导;2)马:细胞内信号转导和前/后模式特化;3)小鼠:DNA甲基化或去甲基化和DNA修饰(图14G)。这些结果揭示了FTW培养所赋予的多能性特征的物种差异,并且可能有助于深入了解体内不同物种之间外胚层发育的进化趋同和发散过程。
实施例11.材料和方法
小鼠
C57BL/6和CD-1(ICR)小鼠购自Charles River或Envigo(Harlen)。129S1/SvImJ和B6(Cg)-Tyrc-2J/J小鼠购自Jackson Laboratory。小鼠在12小时光照/12小时黑暗循环下饲养。所有与动物有关的程序都是按照德克萨斯大学西南医学中心的道德准则进行的。UT西南机构动物护理和使用委员会(IACUC)[协议#2018-102430]审查并批准了动物协议。
小鼠胚胎的收获和培养。
C57BL/6雌性小鼠(8-10周龄)通过腹膜内(IP)注射5IU PMSG(Prospec)超排卵,然后在48小时后通过IP注射5IU hCG。与C57BL/6雄性小鼠交配后,在KSOM-Hepes(Wu等人.,2017)通过冲洗输卵管和子宫角在E2.75[阴道栓的存在被定义为第0.5天胚胎(E0.5)]收获8-细胞至桑葚胚阶段的胚胎。在37℃在含5%(v/v)CO2和5%(v/v)O2的潮湿氛围中在mKSOMaa(Wu等人,2017)中过夜培养胚胎,直至囊胚阶段。自然发情周期中的CD-1雌性(8周龄或更大)与CD-1雄性交配。通过冲洗子宫角在E3.5收获囊胚。
马体细胞核移植(SCNT)胚胎的产生
除非另有说明,否则所有化学品和试剂均购自Sigma Chemical Co.(St.Louis,MO)。
马卵母细胞的收集和体外成熟:来自屠宰场(Mercedes,Buenos Aires)的马卵巢在25℃在添加了0.1mg/mL链霉素的无菌盐水溶液中在3小时内被运送到实验室。对于抽吸,使用连接到真空泵的19G针刺穿直径2-10mm的毛囊。使用收集培养基[具有Hank′s盐、1mg/ml的牛血清白蛋白(BSA)、1mg肝素的T199]将含有卵丘-卵母细胞复合物(COC)的卵泡液收集在无菌50mL离心管(Corning)中。仅选择具有至少三层卵丘细胞的COC用于体外成熟(IVM)。4到45个COC在3mL成熟培养基中培养,并在38.5℃在具有最大湿度的空气中的5%CO2中培养25小时。成熟培养基由补充了1X ITS、0.2mM丙酮酸钠、100μg/mL庆大霉素、10ng/mL Long hIGF、10ng/mL mEGF、0.1IU重组人促卵泡激素(FSH)(Puregón,Organon)和10%(v/v)胎牛血清(FCS)(GIBCO)的M199组成。
体细胞核移植(SCNT):原代成纤维细胞(EF)是从10岁的马球小母马的皮肤活检建立的,并在补充有15%FCS的DMEM高葡萄糖(GIBCO)中在38.5℃在5%CO2和潮湿空气中培养。所有程序均按照稍作修改的Galli C.等人(2006)的描述进行。成熟25小时后,通过在含有1mg/mL透明质酸酶和0.25%胰蛋白酶(v/v;GIBCO)的Hepes缓冲的合成输卵管流体(H-SOF)(补充有20mM HEPES的SOFaa)中涡旋1-2min除去松散关联的卵丘细胞。洗涤裸露的卵母细胞并放回成熟培养基中。在卵母细胞剥脱的30分钟内在带有显微操纵器(NT 88V3,Nikon)的倒置显微镜(Nikon Eclipse Ti,Nikon)下开始去核过程。卵母细胞在添加有1mg/mL Hoechst 33342和5μg/mL细胞松弛素B的H-SOF中于38℃孵育5-10分钟,随后放入操作液滴中(用矿物油和5μg/mL细胞松弛素B覆盖的添加有1%FCS的H-SOF),并在短暂暴露于紫外线(Nikon Filter Set 01,Nikon)后去核以确定DNA的位置。
通过使用0.05%(w/v)胰蛋白酶-EDTA进行胰蛋白酶消化,从培养板收集第3-6代供体EF细胞,洗涤两次,最后重悬于H-SOF中。用转移针拾取细胞并滑入去核卵母细胞的卵周间隙。细胞转移后立即使用覆盖山梨糖醇融合培养基(0.25M甘露醇,0.1mM氯化钙,0.1nM硫酸镁)的0.5mm间隙融合室(BTX,San Diego,CA)使用30μsec的2.7kV/cm脉冲(BTXElectrocell Manipulator ECM 2001,Harvard Apparatus,MA)融合细胞-细胞质对联物。融合后培养基由补充有10%(v/v)FCS的SOF组成。1.5小时后,通过在H-SOF培养基中暴露于8.7μM离子霉素4分钟来激活融合对联物,然后在H-SOF中漂洗3次,并在38.5℃在具有最大湿度的空气中的5%CO2中分配到1mM6-DMAP和5ug/mL放线菌酮中的4-h培养物。此处理后,假定胚胎在H-SOF中漂洗,并在含有10%FCS(Hyclone defined)和8mg/mL BSA(Probumin,Millipore)的Global培养基(Global)中培养7天。
绵羊和山羊体外胚胎生产
COC回收和IVM:绵羊和山羊卵巢采集自Dixon,California的Superior Farm屠宰场。将卵巢在补充有1X青霉素-链霉素溶液的温盐水(~37℃)中运送到实验室。到达实验室后,卵巢在温热的自来水中清洗,并在处理过程中保存在37℃的盐水中。使用连接到真空泵的21G蝶形针从2-6mm窦卵泡中吸出绵羊和山羊COC。真空压力调节至10–12mL/min的流速。选择具有多层卵丘细胞的卵母细胞,洗涤,并在补充有10%(v/v)绵羊发情血清(OES)、绵羊FSH(50ng/mL;National Hormone&Peptide Program,UCLA)、牛LH(3mg/mL;SiouxBiochemical)和半胱胺(0.1mM)的TCM199中在38.5℃下在具有潮湿氛围的5%CO2中体外成熟22小时。
体外受精:将扩增的COC洗涤两次,然后放入由添加2%OES、10μg/mL肝素和10μg/mL亚牛磺酸的SOF组成的受精培养基中。来自新鲜射精的活动精子通过上游法选择,并将其浓度调整为2x106个精子/mL,然后与扩增的COC在38.5℃下在具有潮湿氛围的5%CO2中共同孵育16小时。
体外培养:通过在含有透明质酸酶(1mg/mL)的SOF-Hepes培养基中涡旋3分钟将假定胚胎从周围的卵丘细胞中剥离出来,并用SOF-Hepes洗涤,然后以25个为一组在油下在BO-IVC(IVF Bioscience)的50μL液滴中在38.5℃、5%(v/v)CO2和5%(v/v)O2中培养4天。
猪孤雌胚胎生产
卵母细胞收集和IVM:从当地屠宰场(Olson Meat Company,Orland,CA)收集的青春期前母猪的卵巢的窦卵泡(2-4个直径)吸出卵母细胞。在含有0.1%(w/v)聚乙烯醇(PVA)的TCM-199(GIBCO)中洗涤COC,并在含有0.1%PVA、3.05mM D-葡萄糖、0.91mM丙酮酸钠、0.5μg/mL oFSH、0.5μg/mL bLH、10ng/mL EGF、10μg/mL庆大霉素(GIBCO)和10%(v/v)猪卵泡液的TCM-199中在38℃和5% CO2中培养48h。
孤雌生殖激活:IVM后,通过在1mg/mL透明质酸酶中孵育并轻轻吸移,将成熟卵母细胞的卵丘细胞剥离。裸卵母细胞用含有25mM HEPES(GIBCO)的MEM洗涤,并用120V/mm的两个脉冲电激活40μs,由BTX Electro Cel Manipulator 2001(BTX,San Diego,CA)在含有0.3M甘露醇、0.05mM CaCl2、0.1mM MgSO4和0.1%(w/v)BSA的0.5mm腔室中递送。用PZM-5(Yoshioka等人,2012)洗涤后,将卵母细胞在PZM-5中在5μg/mL细胞松弛素B的存在下孵育3小时,以防止第二极体挤出,从而产生二倍体孤雌生殖胚胎。
胚胎培养:激活后,猪受精卵在含有0.3%BSA的500μL PZM-5(Yoshioka等人,2012)中在38.5℃在5%CO2、5%O2和90%(v/v)N2的湿润气氛中培养3天。
小鼠ESC、EpiSC和FTW-ESC系的衍生和培养
小鼠ESC和EpiSC衍生:胚胎操作在解剖显微镜(Nikon SMZ800N)下进行。简而言之,通过用酸性Tyrode溶液(Millipore MR-004-D)进行短暂处理,从E3.5囊胚中去除透明带(ZP)。去除透明带后,将胚胎接种在补充人白血病抑制因子(LIF)(10ng/mL,Peprotech)、CHIR99021(3μM,Selleckchem)和PD0325901(1μM,Selleckchem)的用于mESC衍生的NB2iL培养基(化学成分确定的N2B27基础培养基(De Los Angeles等人,2019)中或用于EpiSC衍生的NBFR培养基(Wu等人,2015)(补充FGF2(20ng/mL,Peprotech)和IWR1(2.5μM)的N2B27基础培养基)的MEF上。培养4-6天后,使用TrypLE传代ICM长出物并重新播种到新制备的MEF上。人工挑选EpiSC克隆用于进一步培养,以避免滋养层的污染。
从囊胚衍生小鼠FTW-ESC:ZP去除的小鼠囊胚期胚胎[C57BL/6、CD-1(ICR)、129S1/SvImJ和B6(Cg)-Tyrc-2J/J]如上所述获得。然后将胚胎接种在FTW衍生培养基[补充FGF2(10ng/mL,Peprotech)、激活素A(10ng/mL,Peprotech)、CHIR99021(3μM,Selleckchem)和PD0325901(0.5μM,Selleckchem)的N2B27基础培养基]中的MEF上。培养4-6天后,使用TrypLE传代ICM长出物并重新播种到新制备的MEF上。一旦可以观察到均质集落(重新播种后2-3天),将培养基更改为正常FTW培养基[补充FGF2(10ng/mL,Peprotech)、激活素A(10ng/mL,Peprotech)和CHIR99021(3μM,Selleckchem)的N2B27基础培养基]。可选的:可以手动挑选FTW-ESC克隆用于进一步培养,以避免滋养层的污染。
小鼠ESC、FTW-ESC和mEpiSC的培养:建立的小鼠ESC、FTW-ESC和mEpiSC系在MEF包被的板上培养,并且以1:20(mESC)或1:20(FTW-mESC)或1:50(mEpiSC)的分割比每3-4天传代。
FTW-eqESC的衍生
通过胞浆内单精子注射(ICSI)和体细胞核移植(SCNT)生产的玻璃化马囊胚在干燥运货商中发送,并在到达时置于液氮中。如前所述(Y.-H.Choi和Hinrichs,2017),对玻璃化马桑葚胚进行温热。简而言之,胚胎在维持培养基[补充20%FBS的Hanks溶液(GIBCO#12350-039)]中温热,以0.25M、0.15M的递减蔗糖浓度和分别1分钟和5分钟的间隔时间洗涤,然后在维持培养基中孵育5分钟。在具有升温台的倒置显微镜下用Tyrode溶液去除ZP30秒。在5%CO2气氛的37℃加湿培养箱中,在MEF饲养层上在补充10%血清的FTW培养基培养胚胎。胚胎附着后取出血清。未附着于MEF饲养层的膨胀囊胚在无Ca2+、Mg2+的PBS中用微刀片(Shearer精密产品)在倒置显微镜下用显微操作系统进行显微切割,或者在倒置显微镜下在温和的胰蛋白酶消化下解离。明确定义的FTW-eqESC集落被重新接种到新的MEF板中。
使用附加型载体生成FTW-eqiPSC和FTW-hiPSC
马胚胎成纤维细胞是从通过温血母马的经宫颈子宫冲洗收集的23天胚胎中分离出来的。马胎儿成纤维细胞(EFF)细胞和人包皮成纤维细胞(HFF)在成纤维细胞生长培养基(添加10%FBS的DMEM)中培养。附加型质粒:pCXLE-hOCT3/4-shp53(Addgene质粒#27077)、pCXLE-hSK(Addgene质粒#27078)、pCXLE-hUL(Addgene质粒#27080)和pCXLE-EGFP(Addgene质粒#27082)用于重编程(Okita等人,2011)。根据制造商的说明,使用核转染剂(Lonza)将1.5μg的每种附加型质粒(总共6μg)递送到2×106EFF或HFF中。NHDF程序(脉冲代码DT130)和原代细胞P2溶液(用于EFF)和P3溶液(用于HFF)(Lonza)用于核转染。细胞在核转染后5天被胰蛋白酶消化,并重新接种到涂有MEF的100mm培养皿中。第二天用含有10ng/mL bFGF(Peprotech)、10ng/mL激活素A(Peprotech)和3μM ChIR99021(Selleckchem)的N2B27培养基替换培养基。重新播种后在14-24天之间挑选个体集落。
FTW-eqPSC和FTW-hiPSC细胞培养
FTW-eqPSC维持在MEF或Matrigel(BD Biosciences)包被的培养皿上的FTW培养基(提供有10ng/mL bFGF、10ng/mL激活素A和3μM CHIR99021或50ng/ml WNT3a的N2B27培养基)中。细胞在37℃和5%CO2下培养,并且每天更换培养基。对于传代,使用TrypLE Express(GIBCO)将FTW-eqPSC解离为单个细胞,并每3-4天以1:20传代。
碱性磷酸酶(AP)染色
细胞在室温下固定在4%(w/v)PFA中15分钟。AP底物溶液(System Biosciences)是根据制造商的说明制备的。将细胞与AP底物在室温下避光孵育15至20分钟。
核型分析
将细胞在KaryoMAX溶液(GIBCO)中孵育1小时。然后收集细胞并重悬于75μM KCl溶液中。在37℃下孵育30分钟后,将0.5mL固定液(3:1,v/v,甲醇:乙酸)添加到KCl溶液中,并以300g离心10分钟。然后去除上清液,加入5mL冷固定液,然后在冰上孵育30分钟。重复上述步骤,并将最终的细胞悬液滴到载玻片上,并用300nM 4'-6-二脒基-2-苯基吲哚(DAPI)溶液染色。
附加型载体拷贝数检测
附加型载体的拷贝数按照之前的报道进行检测(Okita等人,2011)。简而言之,解离在无饲养层条件下培养的FTW-eqiPSC,或者通过MACS Feeder Removal MicroBeads试剂盒(Miltenyi Biotec)纯化在饲养层上培养的FTW-eqiPSC,并提取基因组DNA用于定量RT-PCR分析。附加型质粒骨架序列(EBNA-1)的引物用于估计所有转染的附加型载体的总拷贝数,eq-GAPDH用于估计细胞数。每个样品中的拷贝数是根据EBNA-1的观察到的Ct值估算的。细胞数是根据观察到的eq-GAPDH Ct值+1估算的,因为每个细胞都有两个GAPDH等位基因。
克隆效率测定
将解离的细胞轻轻地通过40μm细胞过滤器,并以克隆密度(~200个细胞/孔)接种在6孔板中。在经过和未经过10mM Y-27632处理的FTW培养基中培养细胞。10天后计数集落(>20个细胞)。通过将集落数除以铺板的总细胞数来计算克隆效率。
RT-PCR和qRT-PCR分析
按照制造商的说明,使用Rneasy Mini试剂盒(QIAGEN)分离总RNA。基因组DNA通过RNase-Free Dnase Set(QIAGEN)降解。在分光光度计(DS-11+,DeNovix)上测量RNA浓度。总RNA的cDNA使用iScript Reverse Transcription Supermix试剂盒(BIO-RAD)合成,并使用PrimeSTAR GXL DNA聚合酶(TaKaRa)或SYBR Green PCR Master Mix(Thermo FisherScientific)在Touch Thermal Cycler Real-Time PCR系统上进行扩增(C1000,BIO-RAD)。GAPDH表达水平用作内部标准化对照。
RNA FISH
具有Quasar 570染料的小鼠Xist探针购自Biosearch Technologies(SMF-3011-1)。FISH杂交是按照制造商的方案进行的。
细胞群倍增时间
使用倍增时间在线计算器(doubling-time.com/compute.php?lang=en)计算细胞群倍增时间。
胚状体(EB)形成
根据制造商的说明,使用AggreWell 400板(Stem Cell Technologies)生成胚状体(EB)。24小时后,收集形成的EB并在超低附着24孔板(Corning)中培养。1周后,EB被转移到包被Matrigel的培养皿中,并在补充有10%FBS的DMEM培养基中培养另外4-6周。
畸胎瘤形成
将总共5×106个细胞悬浮在50μL DMEM-Matrigel溶液中,并皮下注射到10周龄免疫缺陷NOD-SCID小鼠中。6-8周后,解剖畸胎瘤并用Bouin溶液固定。将石蜡包埋的畸胎瘤切片并用苏木精和曙红染色。
FTW-eqPSC定向分化为心肌细胞
FTW-eqiPSC通过使用先前报道的WiGi方案分化为心肌细胞(Lian等人,2012)。简而言之,FTW培养基被含有B27减去胰岛素补充剂(RPMI/B27-胰岛素,GIBCO)和12μMCHIR99021(Selleckchem)的RPMI 1640培养基取代。1天后,将培养基更换为新鲜的RPMI/B27-胰岛素培养基。第3天,将培养基更换为补充了5μM IWP2(Peprotech)的RPMI/B27-胰岛素培养基。第5天,将培养基更换为新鲜的RPMI/B27-胰岛素培养基。此后,每3天用RPMI1640/B27更换培养基。
FTW-eqPSC定向分化为神经元
为了将FTW-eqiPSC分化为神经元,我们使用了已发布的方案(Shi等人,2012)。简而言之,使用TrypLE将FTW-eqiPSC解离成单个细胞,并在0.1%(w/v)明胶包被的平板中在37℃下放置30分钟以去除MEF。非粘附的FTW-eqiPSC在FTW培养基中以10,000–25,000个细胞/cm2的密度接种在Matrigel包被的板上。允许细胞在FTW培养基中扩增2-3天,直到它们达到80-90%汇合。此时,培养基改为神经诱导培养基,其包含N2B27培养基与10μMSB431542(Tocris)和500ng/ml Noggin(R&D)的1:1混合物。分化8-12天后,使用分散酶(Stemcell)将神经上皮片按1:3的比例传代到N2B27培养基(不含SB431542和头蛋白)中的聚L-鸟氨酸和层粘连蛋白包被的培养皿中。在第12-16天,将20ng/mL的FGF2添加到培养基中2-4天,然后在N2B27培养基中继续培养长达30天。
小鼠、马、绵羊和山羊囊胚的免疫染色
FTW-eqiPSC注射后48小时,囊胚在含有0.1%(w/v)PVA(PVA-PBS)的PBS中洗涤3次,并用Tyrode溶液处理以去除ZP。在PVA-PBS中洗涤3次后,将它们在室温下固定在含有0.1%PVA的4%PFA中30分钟。洗涤三次后,囊胚在PVA-PBS中用1%(v/v)TritonX-100(Fisher BioReagents)透化30分钟,并在含有0.1%TritonX-100的PVA-PBS(洗涤缓冲液)中洗涤三次。在10%(v/v)正常驴血清和0.3%TritonX-100的PVA-PBS中封闭1小时后,囊胚用抗OCT3/4(1:50稀释,sc-365823,Santa Cruz Biotechnology)(用于小鼠囊胚)或抗SOX2(1:50稀释,sc-365823,Santa Cruz Biotechnology)(用于马、绵羊和山羊囊胚)在4℃下孵育过夜。在洗涤缓冲液中冲洗后,将胚胎在Alexa Fluor 488抗小鼠IgG(1:200稀释,A21202,Invitrogen)中室温孵育1小时。洗涤后,囊胚用20μg/mL DAPI复染20分钟,用少量PVA-PBS固定在载玻片上,盖上盖玻片,并使用荧光(Echo Laboratories,CA)或共聚焦显微镜(LSM700,Carl Zeiss)成像。
免疫荧光染色
细胞在4%PFA缓冲液中固定15分钟,并在室温下用PBS中的0.5%Triton X100透化5分钟。细胞用封闭缓冲液[PBS中的5%(v/v)BSA;和0.1%(v/v)Tween 20]封闭1小时,并与在封闭缓冲液中稀释的以下一抗在室温下孵育2小时或在4℃下孵育过夜:抗OCT4(1:50稀释,sc-5279,Santa Cruz Biotechnology),抗-SOX2(1:50稀释,sc-365823,Santa CruzBiotechnology),抗-KLF4(1:500稀释,AF3158,R&D),抗-SSEA1(1:100稀释,sc-21702,Santa Cruz Biotechnology),抗ZO1(1:500稀释,33-9100,Life Technology),抗人β-微管蛋白III(1:50稀释,sc-5274,Santa Cruz Biotechnology),抗心肌肌钙蛋白T(1:400稀释,ab47003,Abcam)和抗甲胎蛋白(10μg/mL,MAB1368,R&D Systems),Lys9(1:100稀释,9753,Cell Signaling),Lys27(1:100稀释,9733,Cell Signaling)。然后,将细胞与二抗(AlexaFluor 488或594驴抗兔或小鼠IgG(1:300稀释,Invitrogen))在封闭缓冲液中室温孵育1小时。最后,在室温下用300nM DAPI溶液对细胞复染20分钟。每一步后,样品用PBS洗涤3次。
免疫印迹
按上述培养条件分离培养的细胞,计数细胞数。用Laemmli样品缓冲液(Bio-Rad)裂解细胞。根据不同的蛋白质大小,细胞裂解物通过运行缓冲液中的10% Bis-Tris蛋白质凝胶或NuPAGE 4%–12%Bis-Tris蛋白质凝胶(Invitrogen)分离。用转移缓冲液将蛋白质电泳转移到0.2μm PVDF膜(1620177,BIO-RAD)中。印迹在室温下在TBS-T+5%脱脂牛奶(Kroger)中封闭1小时,并在4℃下用1%TBS-T BSA中的一抗(1:1000)探测过夜。一抗信息如下:GAPDH(1:1000稀释,M4AB37,Millipore),VINCULIN(1:1000稀释,AB129002,Abcam),OCT4(1:1000稀释,sc-5279,Santa Cruz Biotechnology),NANOG(1:1000稀释,AB5731,Millipore),OTX2(1:1000稀释,AF1979,R&D SYSTERMS),P-SMAD(1:1000稀释,138D4,CellSignaling),p44/42MAPK(1:1000稀释,137F5,Cell Signaling),P-p44/42MAPK(1:1000稀释,9101,Cell Signaling),在TBS-T中洗涤3次后,通过使用与辣根过氧化物酶缀合的第二ELC抗小鼠IgG(1:5000稀释,NXA931V,GE Healthcare LifeScience)或ELC抗兔IgG(1:5000稀释,NA934V,GE Healthcare LifeScience)抗体检测信号。二抗室温孵育1小时。洗涤三次后,使用一块ECL2蛋白印迹底物(80196,Invitrogen)显影,并使用蓝色X射线胶片(F-BX57,Phenix)记录信号。信号由Epson perfection V700 photo扫描,并由Epson扫描软件进行分析。
萤光素酶测定
在24孔板中用2ug TOPFlash或FOPFlash萤光素酶质粒转染细胞(每孔2E5)。36小时后,根据制造商的方案使用双萤光素酶试剂盒(Promega)裂解和分析细胞。
流式细胞术
细胞在37℃下用TrypLE Express解离5分钟。然后,将细胞在室温下在4%多聚甲醛(PFA)中固定30分钟,并在室温下用0.5%v/v triton X-100透化30分钟。然后将细胞在一抗溶液中孵育30分钟,然后在室温下在二抗溶液中孵育30分钟。仅用二抗染色的样品用作阴性对照。最后,将染色的细胞用含2%FBS的PBS洗涤两次,将细胞悬液施加至流式细胞仪(FACScalibur system,BD)。
管腔形成测定
使用如前所述的3D on top方案(Lee等人,2007)诱导细胞以极化并形成管腔。简而言之,au-Slide-8孔ibiTreat板(IB-80826,Ibidi)在37℃下用Matrigel(BDBiosciences)包被1小时。然后将含有10,000个细胞的沉淀重悬于50μL冰冷Matrigel(BDBiosciences)中。将溶液滴入aμ-Slide8孔ibiTreat板的孔中,并在37℃下孵育5分钟。然后向孔中加入300μL培养基。
原始生殖细胞样细胞(PGC-LC)诱导
从mESC的PGC诱导是按照已发布的方案(Hayashi和Saitou,2013)进行的。对于PGC-LC诱导,将1.5x103个细胞(小鼠FTW-PSC或EpiLC)或3.0x103个细胞(马FTW-PSC)接种到低细胞结合U型底96孔板(NUNC)的每个孔中的PGC-LC诱导培养基中:含有GMEM、15%(v/v)KnockOut血清替代物、0.1mM丙酮酸钠、0.1mM NEAA、0.1mM b-巯基乙醇、2mM Glutamax和100U/mL青霉素的GK15培养基,补充有500ng/mL(小鼠FTW-PSC和EpiLC)或200ng/mL(FTW-eqPSC)BMP4(GIBCO)、LIF(1000U/mL;Peprotech)、SCF(100ng/mL;R&D)和EGF(50ng/mL;Peprotech)。在一些实验中,添加的抑制剂包括PD173017(100ng/mL;Selleckchem)、SB431542(10μM;Tocris)、IWR1(2.5μM;Sigma)或吡啶-6(1μM;Sigma)。
FTW-PSC的囊胚注射
将FTW-PSC注射到小鼠囊胚中如前所述(Wu等人,2017)在稍作修改的情况下进行。简而言之,将FTW-PSC的单细胞悬浮液添加到含有囊胚的40μL KSOM-Hepes液滴中,并置于装有显微操纵器(Narishige)的倒置显微镜(Leica)上。将个体细胞收集到内径(ID)为15–20μm的微量移液器中,并使用压电微型操纵器(Prime Tech)在小鼠囊胚的透明带和滋养外胚层中打孔。十个(FTW-mESC)或十五个(FTW-eqiPSC)或十二个(FTW-eqESC)细胞被引入囊胚腔。显微注射后,囊胚在mKSOMaa中培养。在注射后24和48小时使用倒置荧光显微镜(Nikon)观察荧光信号。
对于小鼠胚胎移植,8-12周龄的ICR雌性小鼠用作代孕者,并与输精管结扎的ICR雄性小鼠交配以诱导假妊娠。氯胺酮(30mg/ml)和丁丙诺啡(1mg/ml)在手术中用于维持麻醉和止痛。注射的胚胎在E2.5时被转移到代孕子宫。每个代孕者在20-30分钟内转移并执行14-30个囊胚。
为了将FTW-eqiPSC注射到马囊胚中,简而言之,将FTW-eqiPSC的单细胞悬浮液添加到含有囊胚的40μL KSOM-Hepes液滴中。将个体细胞收集到20μm ID的微量移液器中。使用激光系统(Saturn 5Active,Research Instruments)在透明带和滋养外胚层中创建一个整体。十个细胞被引入囊胚腔。显微注射后,囊胚在FTW培养基中的MEF上培养48小时。在注射后24小时和48小时使用倒置荧光显微镜观察荧光信号并成像。
对于绵羊、山羊和猪桑葚注射液,对于猪在第3-4天和对于绵羊和山羊胚胎在第4天选择具有超过8个分裂球且压实前的胚胎。将单细胞悬浮液添加到含有待注射胚胎的50μL细胞培养基液滴中,并放置在装有显微操作器的倒置显微镜上。将个体细胞收集到20–30μm ID的微量移液器中。然后,使用激光系统在胚胎的透明带中创建一个整体。然后,10个细胞沉积在分裂球之间。细胞注射后,胚胎在每种细胞培养基和胚胎培养基的混合培养基(1:1)中培养。在培养期结束时,使用倒置荧光显微镜(Nikon)观察hKO信号,然后固定胚胎用于免疫染色。
嵌合胚胎的免疫染色和成像
在E13.5(对于FTW-mESC)或E7.75/E9.5(对于FTW-eqESC),代孕者被安乐死,并分离胚胎。将胚胎浸入4%多聚甲醛中,并在4℃下孵育1小时(小型胚胎)或过夜(正常大小胚胎)。在30%蔗糖溶液(Fisher)中过夜冷冻保护后,将胚胎包埋在Polyfreeze组织冷冻培养基(Polyscience,Inc)中并在干冰中冷冻。在Leica低温恒温器(Leica CM1950)上切割不同胚胎的切片(小型胚胎为10-12mm厚,正常大小胚胎为20mm厚)。对于免疫染色,我们使用标准染色程序和10mM柠檬酸盐缓冲液(基于0.05%tween20)用于抗原修复。使用的一抗如下:鸡抗GFP(AVES实验室,1:300)、小鼠抗TuJ1(Santa Cruz,1:50)、小鼠抗巢蛋白(SantaCruz,1:50)、兔抗T(Abcam,1:1000),兔抗cTNT(Abcam,1:100),小鼠抗SMA(Abcam,1:300),小鼠抗SOX17(Santa Cruz,1:50),兔抗FOXA2(Cell Signaling,1:200),小鼠抗-AFP(R&D,1:100),兔抗-PAX6(Santa Cruz,1:100)。嵌合体胚胎的成像是用配备有Plan-Neofluar Z1.0x/0.25(FWD 56mm)物镜和Axiocam 503单色相机的Zeiss Axio Zoom.V16荧光立体变焦显微镜进行的。所有照片都是使用相同的光圈、曝光和增益采集设置拍摄的。使用ZEN PRO2012(蓝色版,ZEISS)软件2.3对荧光EGFP图像进行伪彩色处理。
植入后小鼠胚胎体外培养
使用已发布的方案(Bedzhov等人,2014),将小鼠胚胎体外培养至植入后阶段。简而言之,将注射细胞的小鼠胚胎接种在au-Slide-8孔ibiTreat板(IB-80826,Ibidi)上的IVC1培养基中:补充有20%(v/v)热灭活FCS、2mM Glutamax(GIBCO)、1×ITS-X(ThermoFisher)、8nMβ-雌二醇、200ng/ml黄体酮和25μM N-乙酰基-1-半胱氨酸的高级DMEM/F12。胚胎附着后,将培养基更换为IVC2培养基:补充30%(v/v)KSR、2mM Glutamax、1×ITS-X、8nMβ-雌二醇、200ng/ml黄体酮和25μM N-乙酰基-1-半胱氨酸的DMEM/F12。之后,每两天更换一次IVC2培养基。
RNA测序
使用Rneasy Mini试剂盒(QIAGEN)使用DNase处理(QIAGEN)进行RNA提取。使用2100生物分析仪(Aglient Technologies)分析RNA。(每百万千碱基的转录物)。使用具有参数“-k 1--no-unal--dta--rna-strandness R”的HISAT2(版本2.1.0)(Kim等人,2015)将RNA-seq读数映射到小鼠基因组(GRCm38.p6)和马基因组(EquCab3.0)。然后使用具有参数“--rf-t-e-B-A”的StringTie(v1.3.3b)(Pertea等人,2015)计算基因表达水平。表达水平的2倍方差、小于0.05的P值和小于0.1的调整后的P值被用作定义差异表达基因的截止值。使用DESeq2(Love等人,2014)计算P值和调整后的P值。GO分析在Metascape(metascape.org)上进行。
ChIP测序
细胞在37℃下用TrypLE Express解离5分钟,然后用冰冷的PBS冲洗。细胞在室温下在新鲜的1%PFA中交联8分钟。交联通过甘氨酸(最终浓度0.125M)淬灭,样品在室温下放置在旋转器上另外10分钟。通过在4℃下以2000g离心10分钟来收集细胞。去除上清液并用冰冷的PBS冲洗细胞。通过用手指轻弹管子脱落沉淀物。然后通过在4℃下以2000g离心10分钟收获细胞并弃去上清液。在液氮中快速冷冻细胞沉淀并储存在-80℃。ChiP通过使用用于组蛋白的Diagenode iDeal ChIP-seq试剂盒(C01010059,Diagenode)进行。用针对H3K4me3(A1052D,Diagenode)和H3K27me3(A0821D,Diagenode)的抗体对溶解的染色质进行免疫沉淀。通过使用NEBNext Ultra II DNA文库制备试剂盒(E7645L,NEB)制备文库。使用具有参数“-k 1-q”的bowtie2(版本2.3.4.3)(Ben Langmead和Salzberg,2012)将ChIP-seq读数映射到小鼠基因组(GRCm38.p6)和马基因组(EquCab3.0)。然后使用Samtools rmdup(版本1.5)(H.Li等人,2009)删除潜在的PCR重复项。使用具有参数“-t-c-g-B-p 0.001”的MACS2(版本2.1.1.20160309)(Y.Zhang等人,2008)执行峰值调用。使用ChIPseeker(v1.18.0)(Yu等人,2015)对峰进行注释。
RNA-seq和ChIP-seq数据的可视化
使用Integrative Genomics Viewer(IGV,版本2.3.88)(Robinson等人,2011)可视化转录组和ChIP-seq数据集。
统计分析
所有定量数据均以平均值±SD表示。实验至少重复三次(重复次数在图例中指示为“n”)。通过使用Prism(GraphPad Software)的多重t检验分析进行统计分析。小于0.05的P值被认为具有统计学意义。
实施例12.人、犀牛和猪iPSC或ESC的成功衍生。
进行了对人、犀牛和猪PSC的FTW-PSC培养条件进的一步优化。
对于人FTW-PSC细胞,在根据实施例8和11中描述的方法衍生多能细胞后,在存在或不存在JNK抑制剂(SP600125,0.5μM、2μM或5μM)的情况下培养人FTW-PSC细胞。图15A显示了在JNK抑制剂的存在下培养的细胞的代表性明场图像,图15B显示了包括JNK抑制剂以剂量依赖性方式极大地增加了人FTW-PSC的生长(例如,减少的倍增时间)。人FTW-PSC也表达了与预期相同的多能性标志物(例如,OCT4和SOX2),如图15C所示。
为了测试FTW-PSC方案是否适用于稀有物种,FTW-iPSC使用与人FTW-iPSC相同的方案(参见实施例8和11)衍生自犀牛终末细胞(成纤维细胞)。这些细胞有效生长(图15D)并表达多能性标志物(OCT4和SOX2)(图15E)。
最后,如前所述,使用FTW-PSC方案衍生猪FTW-PSC。简而言之,将白血病抑制因子(LIF)添加到分化培养基和培养基中。在这个实验中,显示了FTW条件加上白血病抑制因子(LiF)使得能够从猪囊胚衍生猪ESC(图15F-15G)。
等同物
虽然已在本文中描述和说明了几个本发明的实施方案,但本领域普通技术人员将容易地设想用于进行所述功能和/或获得本文所述的结果和/或一个或多个有利方面的各种其它方法和/或结构,并且这样的变化和/或修改的每一种被认为在本文所述的本发明的实施方案的范围内。更通常地,本领域技术人员将容易地理解,本文所述的所有参数、尺度、材料和构型意欲为示例性的并且实际参数、尺度、材料和/或构型将取决于对其使用本发明的教导的具体应用。本领域技术人员将认可或能够确定本文所述的特定的本发明的实施方案的许多等同物(通过使用不超过常规实验)。因此,应理解,前述实施方案仅通过举例的方式提出,并且在所附权利要求和其等同物的范围内,本发明的实施方案可按与明确描述和要求保护的方式不同的方式来实施。本公开内容的本发明的实施方案涉及本文所述的各种个体特性、系统、物品、材料、试剂盒和/或方法。另外,如果这样的特性、系统、物品、材料、试剂盒和/或方法不是相互矛盾的,则两个或更多个这样的特性、系统、物品、材料、试剂盒和/或方法的任意组合包括在本公开内容的发明范围内。
如本文中所定义和使用的,所有定义应当被理解为优先于词典定义、通过引用并入的文献中的定义和/或所定义的术语的一般含义。
本文中公开的所有参考文献、专利和专利申请在关于引用其每一个的主题方面通过引用并入本文,这在一些情况下可包括文献的完整内容。
除非明确地指示与之相反,否则不定冠词“a”和“an”,如本文中在说明书和权利要求中所用,应当被理解为意指“至少一种/一个”。
短语“和/或”,如在本文中在说明书和权利要求中所用,应当被理解为意指所连接的元素的“任一个或两者”,即元素在一些情况下结合地存在以及在其它情况下分离地存在。利用“和/或”列出的多个元素应当以相同的方式来解释,即所连接的元素的“一个或多个”。除通过“和/或”从句明确确定的元素外,还可任选地存在其它元素,无论与明确确定的那些元素相关还是无关。因此,作为非限定性实例,对“A和/或B”的提及,当与开放性措辞诸如“包含/包括”结合使用时,在一个实施方案中可仅指A(任选地包括除B外的元素);在另一个实施方案中可仅指B(任选地包括除A外的元素);在另一个实施方案中,可指A和B(任选地包括其它元素);依此类推。
如本文中在说明书和权利要求中所用,“或”应当被理解为具有与如上定义的“和/或”相同的含义。例如,当在列表中分开各项时,“或”或“和/或”应当被理解为是包含性的,即包含至少一个,但也包括许多个元素或一列元素中的多于一个,以及任选地,包括另外未列出的项。只有明确地指明相反的术语,例如“……中的仅一个”或“……中的恰好一个”或当用于权利要求中时的“由……组成”将指包含多个元素或一列元素中的正好一个元素。一般地,如本文中所用的术语“或”应当仅在冠有排他性的术语诸如“任一”、“……之一”、“……中的仅一个”或“……中的恰好一个”时被解释为表示排他性选择(即“一个或另一个但非两个”)。“基本上由……组成”,当用于权利要求中时,应当具有其在专利法领域中使用的普通含义。
如本文中在说明书和权利要求中所用,关于一列一个或多个元素的短语“至少一个”应当被理解为意指选自一列元素中的任何一个或多个元素的至少一个元素,但不一定包括元素列表内明确列出的每一个元素的至少一个并且不排除元素列表中的元素的任何组合。该定义还允许可任选地存在除短语“至少一个”所指的元素列表内明确确定的元素外的元素,无论与那些明确确定的元素相关还是不相关。因此,作为非限定性实例,“A和B的至少一个”(或,等同地,“A或B的至少一个”或,等同地“A和/或B的至少一个”)可在一个实施方案中指至少一个(任选地包括不止一个)A而无B存在(且任选地包括除B外的元素);在另一个实施方案中指至少一个(任选地包括不止一个)B而无A存在(且任选地包括除A外的元素);在另一个实施方案中指至少一个(任选地包括不止一个)A和至少一个(任选地包括不止一个)B(且任选地包括其它元素);依此类推。
还应当理解,除非明确地指明与之相反,否则在包括不止一个步骤或行为的本文请求保护的任何方法中,所述方法的步骤或行为的顺序不必须地限定于其中叙述所述方法的步骤或行为的顺序。
在说明书和权利要求书中使用的不定冠词“a”和“an”,除非有相反的明确指示,否则应理解为“至少一种/一个”。
说明书和权利要求书中所用的短语“和/或”应理解为意指所连接的元素的“任一个或两者”,即元素在一些情况下结合地存在以及在其它情况下分离地存在。利用“和/或”列出的多个元素应当以相同的方式来解释,即所连接的元素的“一个或多个”。除通过“和/或”从句明确确定的元素外,还可任选地存在其它元素,无论与明确确定的那些元素相关还是无关。因此,作为非限定性实例,对“A和/或B”的提及,当与开放性措辞诸如“包含/包括”结合使用时,在一个实施方案中可仅指A(任选地包括除B外的元素);在另一个实施方案中可仅指B(任选地包括除A外的元素);在另一个实施方案中,可指A和B(任选地包括其它元素);依此类推。
如本文中在说明书和权利要求中所用,“或”应当被理解为具有与如上定义的“和/或”相同的含义。例如,当在列表中分开各项时,“或”或“和/或”应当被理解为是包含性的,即包含至少一个,但也包括许多个元素或一列元素中的多于一个,以及任选地,包括另外未列出的元素。
序列表
<110> 得克萨斯大学体系董事会
<120> 用于产生能够直接诱导原始生殖细胞的形成性多能干细胞的方法
<130> 106546-703050 (UTSD 3709-PCT)
<150> 63/093,680
<151> 2020-10-19
<160> 8
<170> PatentIn version 3.5
<210> 1
<211> 6774
<212> DNA
<213> 智人
<400> 1
cggccccaga aaacccgagc gagtaggggg cggcgcgcag gagggaggag aactgggggc 60
gcgggaggct ggtgggtgtg gggggtggag atgtagaaga tgtgacgccg cggcccggcg 120
ggtgccagat tagcggacgc ggtgcccgcg gttgcaacgg gatcccgggc gctgcagctt 180
gggaggcggc tctccccagg cggcgtccgc ggagacaccc atccgtgaac cccaggtccc 240
gggccgccgg ctcgccgcgc accaggggcc ggcggacaga agagcggccg agcggctcga 300
ggctggggga ccgcgggcgc ggccgcgcgc tgccgggcgg gaggctgggg ggccggggcc 360
ggggccgtgc cccggagcgg gtcggaggcc ggggccgggg ccgggggacg gcggctcccc 420
gcgcggctcc agcggctcgg ggatcccggc cgggccccgc agggaccatg gcagccggga 480
gcatcaccac gctgcccgcc ttgcccgagg atggcggcag cggcgccttc ccgcccggcc 540
acttcaagga ccccaagcgg ctgtactgca aaaacggggg cttcttcctg cgcatccacc 600
ccgacggccg agttgacggg gtccgggaga agagcgaccc tcacatcaag ctacaacttc 660
aagcagaaga gagaggagtt gtgtctatca aaggagtgtg tgctaaccgt tacctggcta 720
tgaaggaaga tggaagatta ctggcttcta aatgtgttac ggatgagtgt ttcttttttg 780
aacgattgga atctaataac tacaatactt accggtcaag gaaatacacc agttggtatg 840
tggcactgaa acgaactggg cagtataaac ttggatccaa aacaggacct gggcagaaag 900
ctatactttt tcttccaatg tctgctaaga gctgatttta atggccacat ctaatctcat 960
ttcacatgaa agaagaagta tattttagaa atttgttaat gagagtaaaa gaaaataaat 1020
gtgtatagct cagtttggat aattggtcaa acaatttttt atccagtagt aaaatatgta 1080
accattgtcc cagtaaagaa aaataacaaa agttgtaaaa tgtatattct cccttttata 1140
ttgcatctgc tgttacccag tgaagcttac ctagagcaat gatctttttc acgcatttgc 1200
tttattcgaa aagaggcttt taaaatgtgc atgtttagaa acaaaatttc ttcatggaaa 1260
tcatatacat tagaaaatca cagtcagatg tttaatcaat ccaaaatgtc cactatttct 1320
tatgtcattc gttagtctac atgtttctaa acatataaat gtgaatttaa tcaattcctt 1380
tcatagtttt ataattctct ggcagttcct tatgatagag tttataaaac agtcctgtgt 1440
aaactgctgg aagttcttcc acagtcaggt caattttgtc aaacccttct ctgtacccat 1500
acagcagcag cctagcaact ctgctggtga tgggagttgt attttcagtc ttcgccaggt 1560
cattgagatc catccactca catcttaagc attcttcctg gcaaaaattt atggtgaatg 1620
aatatggctt taggcggcag atgatataca tatctgactt cccaaaagct ccaggatttg 1680
tgtgctgttg ccgaatactc aggacggacc tgaattctga ttttatacca gtctcttcaa 1740
aaacttctcg aaccgctgtg tctcctacgt aaaaaaagag atgtacaaat caataataat 1800
tacactttta gaaactgtat catcaaagat tttcagttaa agtagcatta tgtaaaggct 1860
caaaacatta ccctaacaaa gtaaagtttt caatacaaat tctttgcctt gtggatatca 1920
agaaatccca aaatattttc ttaccactgt aaattcaaga agcttttgaa atgctgaata 1980
tttctttggc tgctacttgg aggcttatct acctgtacat ttttggggtc agctcttttt 2040
aacttcttgc tgctcttttt cccaaaaggt aaaaatatag attgaaaagt taaaacattt 2100
tgcatggctg cagttccttt gtttcttgag ataagattcc aaagaactta gattcatttc 2160
ttcaacaccg aaatgctgga ggtgtttgat cagttttcaa gaaacttgga atataaataa 2220
ttttataatt caacaaaggt tttcacattt tataaggttg atttttcaat taaatgcaaa 2280
tttgtgtggc aggattttta ttgccattaa catatttttg tggctgcttt ttctacacat 2340
ccagatggtc cctctaactg ggctttctct aattttgtga tgttctgtca ttgtctccca 2400
aagtatttag gagaagccct ttaaaaagct gccttcctct accactttgc tggaaagctt 2460
cacaattgtc acagacaaag atttttgttc caatactcgt tttgcctcta tttttcttgt 2520
ttgtcaaata gtaaatgata tttgcccttg cagtaattct actggtgaaa aacatgcaaa 2580
gaagaggaag tcacagaaac atgtctcaat tcccatgtgc tgtgactgta gactgtctta 2640
ccatagactg tcttacccat cccctggata tgctcttgtt ttttccctct aatagctatg 2700
gaaagatgca tagaaagagt ataatgtttt aaaacataag gcattcgtct gccatttttc 2760
aattacatgc tgacttccct tacaattgag atttgcccat aggttaaaca tggttagaaa 2820
caactgaaag cataaaagaa aaatctaggc cgggtgcagt ggctcatgcc tatattccct 2880
gcactttggg aggccaaagc aggaggatcg cttgagccca ggagttcaag accaacctgg 2940
tgaaaccccg tctctacaaa aaaacacaaa aaatagccag gcatggtggc gtgtacatgt 3000
ggtctcagat acttgggagg ctgaggtggg agggttgatc acttgaggct gagaggtcaa 3060
ggttgcagtg agccataatc gtgccactgc agtccagcct aggcaacaga gtgagacttt 3120
gtctcaaaaa aagagaaatt ttccttaata agaaaagtaa tttttactct gatgtgcaat 3180
acatttgtta ttaaatttat tatttaagat ggtagcacta gtcttaaatt gtataaaata 3240
tcccctaaca tgtttaaatg tccattttta ttcattatgc tttgaaaaat aattatgggg 3300
aaatacatgt ttgttattaa atttattatt aaagatagta gcactagtct taaatttgat 3360
ataacatctc ctaacttgtt taaatgtcca tttttattct ttatgtttga aaataaatta 3420
tggggatcct atttagctct tagtaccact aatcaaaagt tcggcatgta gctcatgatc 3480
tatgctgttt ctatgtcgtg gaagcaccgg atgggggtag tgagcaaatc tgccctgctc 3540
agcagtcacc atagcagctg actgaaaatc agcactgcct gagtagtttt gatcagttta 3600
acttgaatca ctaactgact gaaaattgaa tgggcaaata agtgcttttg tctccagagt 3660
atgcgggaga cccttccacc tcaagatgga tatttcttcc ccaaggattt caagatgaat 3720
tgaaattttt aatcaagata gtgtgcttta ttctgttgta ttttttatta ttttaatata 3780
ctgtaagcca aactgaaata acatttgctg ttttataggt ttgaagaaca taggaaaaac 3840
taagaggttt tgtttttatt tttgctgatg aagagatatg tttaaatatg ttgtattgtt 3900
ttgtttagtt acaggacaat aatgaaatgg agtttatatt tgttatttct attttgttat 3960
atttaataat agaattagat tgaaataaaa tataatggga aataatctgc agaatgtggg 4020
ttttcctggt gtttccctct gactctagtg cactgatgat ctctgataag gctcagctgc 4080
tttatagttc tctggctaat gcagcagata ctcttcctgc cagtggtaat acgatttttt 4140
aagaaggcag tttgtcaatt ttaatcttgt ggataccttt atactcttag ggtattattt 4200
tatacaaaag ccttgaggat tgcattctat tttctatatg accctcttga tatttaaaaa 4260
acactatgga taacaattct tcatttacct agtattatga aagaatgaag gagttcaaac 4320
aaatgtgttt cccagttaac tagggtttac tgtttgagcc aatataaatg tttaactgtt 4380
tgtgatggca gtattcctaa agtacattgc atgttttcct aaatacagag tttaaataat 4440
ttcagtaatt cttagatgat tcagcttcat cattaagaat atcttttgtt ttatgttgag 4500
ttagaaatgc cttcatatag acatagtctt tcagacctct actgtcagtt ttcatttcta 4560
gctgctttca gggttttatg aattttcagg caaagcttta atttatacta agcttaggaa 4620
gtatggctaa tgccaacggc agtttttttc ttcttaattc cacatgactg aggcatatat 4680
gatctctggg taggtgagtt gttgtgacaa ccacaagcac tttttttttt tttaaagaaa 4740
aaaaggtagt gaatttttaa tcatctggac tttaagaagg attctggagt atacttaggc 4800
ctgaaattat atatatttgg cttggaaatg tgtttttctt caattacatc tacaagtaag 4860
tacagctgaa attcagagga cccataagag ttcacatgaa aaaaatcaat ttatttgaaa 4920
aggcaagatg caggagagag gaagccttgc aaacctgcag actgcttttt gcccaatata 4980
gattgggtaa ggctgcaaaa cataagctta attagctcac atgctctgct ctcacgtggc 5040
accagtggat agtgtgagag aattaggctg tagaacaaat ggccttctct ttcagcattc 5100
acaccactac aaaatcatct tttatatcaa cagaagaata agcataaact aagcaaaagg 5160
tcaataagta cctgaaacca agattggcta gagatatatc ttaatgcaat ccattttctg 5220
atggattgtt acgagttggc tatataatgt atgtatggta ttttgatttg tgtaaaagtt 5280
ttaaaaatca agctttaagt acatggacat ttttaaataa aatatttaaa gacaatttag 5340
aaaattgcct taatatcatt gttggctaaa tagaataggg gacatgcata ttaaggaaaa 5400
ggtcatggag aaataatatt ggtatcaaac aaatacattg atttgtcatg atacacattg 5460
aatttgatcc aatagtttaa ggaataggta ggaaaatttg gtttctattt ttcgatttcc 5520
tgtaaatcag tgacataaat aattcttagc ttattttata tttccttgtc ttaaatactg 5580
agctcagtaa gttgtgttag gggattattt ctcagttgag actttcttat atgacatttt 5640
actatgtttt gacttcctga ctattaaaaa taaatagtag atacaatttt cataaagtga 5700
agaattatat aatcactgct ttataactga ctttattata tttatttcaa agttcattta 5760
aaggctacta ttcatcctct gtgatggaat ggtcaggaat ttgttttctc atagtttaat 5820
tccaacaaca atattagtcg tatccaaaat aacctttaat gctaaacttt actgatgtat 5880
atccaaagct tctcattttc agacagatta atccagaagc agtcataaac agaagaatag 5940
gtggtatgtt cctaatgata ttatttctac taatggaata aactgtaata ttagaaatta 6000
tgctgctaat tatatcagct ctgaggtaat ttctgaaatg ttcagactca gtcggaacaa 6060
attggaaaat ttaaattttt attcttagct ataaagcaag aaagtaaaca cattaatttc 6120
ctcaacattt ttaagccaat taaaaatata aaagatacac accaatatct tcttcaggct 6180
ctgacaggcc tcctggaaac ttccacatat ttttcaactg cagtataaag tcagaaaata 6240
aagttaacat aactttcact aacacacaca tatgtagatt tcacaaaatc cacctataat 6300
tggtcaaagt ggttgagaat atatttttta gtaattgcat gcaaaatttt tctagcttcc 6360
atcctttctc cctcgtttct tctttttttg ggggagctgg taactgatga aatcttttcc 6420
caccttttct cttcaggaaa tataagtggt tttgtttggt taacgtgata cattctgtat 6480
gaatgaaaca ttggagggaa acatctactg aatttctgta atttaaaata ttttgctgct 6540
agttaactat gaacagatag aagaatctta cagatgctgc tataaataag tagaaaatat 6600
aaatttcatc actaaaatat gctattttaa aatctatttc ctatattgta tttctaatca 6660
gatgtattac tcttattatt tctattgtat gtgttaatga ttttatgtaa aaatgtaatt 6720
gcttttcatg agtagtatga ataaaattga ttagtttgtg ttttcttgtc tccc 6774
<210> 2
<211> 288
<212> PRT
<213> 智人
<400> 2
Met Val Gly Val Gly Gly Gly Asp Val Glu Asp Val Thr Pro Arg Pro
1 5 10 15
Gly Gly Cys Gln Ile Ser Gly Arg Gly Ala Arg Gly Cys Asn Gly Ile
20 25 30
Pro Gly Ala Ala Ala Trp Glu Ala Ala Leu Pro Arg Arg Arg Pro Arg
35 40 45
Arg His Pro Ser Val Asn Pro Arg Ser Arg Ala Ala Gly Ser Pro Arg
50 55 60
Thr Arg Gly Arg Arg Thr Glu Glu Arg Pro Ser Gly Ser Arg Leu Gly
65 70 75 80
Asp Arg Gly Arg Gly Arg Ala Leu Pro Gly Gly Arg Leu Gly Gly Arg
85 90 95
Gly Arg Gly Arg Ala Pro Glu Arg Val Gly Gly Arg Gly Arg Gly Arg
100 105 110
Gly Thr Ala Ala Pro Arg Ala Ala Pro Ala Ala Arg Gly Ser Arg Pro
115 120 125
Gly Pro Ala Gly Thr Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala
130 135 140
Leu Pro Glu Asp Gly Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys
145 150 155 160
Asp Pro Lys Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile
165 170 175
His Pro Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser Asp Pro His
180 185 190
Ile Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys
195 200 205
Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu
210 215 220
Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu
225 230 235 240
Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp
245 250 255
Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr
260 265 270
Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser
275 280 285
<210> 3
<211> 4704
<212> DNA
<213> 智人
<400> 3
ggagagggag aaggctctcg ggcggagaga ggtcctgccc agctgttggc gaggagtttc 60
ctgtttcccc cgcagcgctg agttgaagtt gagtgagtca ctcgcgcgca cggagcgacg 120
acacccccgc gcgtgcaccc gctcgggaca ggagccggac tcctgtgcag cttccctcgg 180
ccgccggggg cctccccgcg cctcgccggc ctccaggccc cctcctggct ggcgagcggg 240
cgccacatct ggcccgcaca tctgcgctgc cggcccggcg cggggtccgg agagggcgcg 300
gcgcggaggc gcagccaggg gtccgggaag gcgccgtccg ctgcgctggg ggctcggtct 360
atgacgagca gcggggtctg ccatgggtcg ggggctgctc aggggcctgt ggccgctgca 420
catcgtcctg tggacgcgta tcgccagcac gatcccaccg cacgttcaga agtcggatgt 480
ggaaatggag gcccagaaag atgaaatcat ctgccccagc tgtaatagga ctgcccatcc 540
actgagacat attaataacg acatgatagt cactgacaac aacggtgcag tcaagtttcc 600
acaactgtgt aaattttgtg atgtgagatt ttccacctgt gacaaccaga aatcctgcat 660
gagcaactgc agcatcacct ccatctgtga gaagccacag gaagtctgtg tggctgtatg 720
gagaaagaat gacgagaaca taacactaga gacagtttgc catgacccca agctccccta 780
ccatgacttt attctggaag atgctgcttc tccaaagtgc attatgaagg aaaaaaaaaa 840
gcctggtgag actttcttca tgtgttcctg tagctctgat gagtgcaatg acaacatcat 900
cttctcagaa gaatataaca ccagcaatcc tgacttgttg ctagtcatat ttcaagtgac 960
aggcatcagc ctcctgccac cactgggagt tgccatatct gtcatcatca tcttctactg 1020
ctaccgcgtt aaccggcagc agaagctgag ttcaacctgg gaaaccggca agacgcggaa 1080
gctcatggag ttcagcgagc actgtgccat catcctggaa gatgaccgct ctgacatcag 1140
ctccacgtgt gccaacaaca tcaaccacaa cacagagctg ctgcccattg agctggacac 1200
cctggtgggg aaaggtcgct ttgctgaggt ctataaggcc aagctgaagc agaacacttc 1260
agagcagttt gagacagtgg cagtcaagat ctttccctat gaggagtatg cctcttggaa 1320
gacagagaag gacatcttct cagacatcaa tctgaagcat gagaacatac tccagttcct 1380
gacggctgag gagcggaaga cggagttggg gaaacaatac tggctgatca ccgccttcca 1440
cgccaagggc aacctacagg agtacctgac gcggcatgtc atcagctggg aggacctgcg 1500
caagctgggc agctccctcg cccgggggat tgctcacctc cacagtgatc acactccatg 1560
tgggaggccc aagatgccca tcgtgcacag ggacctcaag agctccaata tcctcgtgaa 1620
gaacgaccta acctgctgcc tgtgtgactt tgggctttcc ctgcgtctgg accctactct 1680
gtctgtggat gacctggcta acagtgggca ggtgggaact gcaagataca tggctccaga 1740
agtcctagaa tccaggatga atttggagaa tgttgagtcc ttcaagcaga ccgatgtcta 1800
ctccatggct ctggtgctct gggaaatgac atctcgctgt aatgcagtgg gagaagtaaa 1860
agattatgag cctccatttg gttccaaggt gcgggagcac ccctgtgtcg aaagcatgaa 1920
ggacaacgtg ttgagagatc gagggcgacc agaaattccc agcttctggc tcaaccacca 1980
gggcatccag atggtgtgtg agacgttgac tgagtgctgg gaccacgacc cagaggcccg 2040
tctcacagcc cagtgtgtgg cagaacgctt cagtgagctg gagcatctgg acaggctctc 2100
ggggaggagc tgctcggagg agaagattcc tgaagacggc tccctaaaca ctaccaaata 2160
gctcttctgg ggcaggctgg gccatgtcca aagaggctgc ccctctcacc aaagaacaga 2220
ggcagcagga agctgcccct gaactgatgc ttcctggaaa accaaggggg tcactcccct 2280
ccctgtaagc tgtggggata agcagaaaca acagcagcag ggagtgggtg acatagagca 2340
ttctatgcct ttgacattgt cataggataa gctgtgttag cacttcctca ggaaatgaga 2400
ttgattttta caatagccaa taacatttgc actttattaa tgcctgtata taaatatgaa 2460
tagctatgtt ttatatatat atatatatat ctatatatgt ctatagctct atatatatag 2520
ccataccttg aaaagagaca aggaaaaaca tcaaatattc ccaggaaatt ggttttattg 2580
gagaactcca gaaccaagca gagaaggaag ggacccatga cagcattagc atttgacaat 2640
cacacatgca gtggttctct gactgtaaaa cagtgaactt tgcatgagga aagaggctcc 2700
atgtctcaca gccagctatg accacattgc acttgctttt gcaaaataat cattccctgc 2760
ctagcacttc tcttctggcc atggaactaa gtacagtggc actgtttgag gaccagtgtt 2820
cccggggttc ctgtgtgccc ttatttctcc tggacttttc atttaagctc caagccccaa 2880
atctgggggg ctagtttaga aactctccct caacctagtt tagaaactct accccatctt 2940
taataccttg aatgttttga accccacttt ttaccttcat gggttgcaga aaaatcagaa 3000
cagatgtccc catccatgcg attgccccac catctactaa tgaaaaattg ttcttttttt 3060
catctttccc ctgcacttat gttactattc tctgctccca gccttcatcc ttttctaaaa 3120
aggagcaaat tctcactcta ggctttatcg tgtttacttt ttcattacac ttgacttgat 3180
tttctagttt tctatacaaa caccaatggg ttccatcttt ctgggctcct gattgctcaa 3240
gcacagtttg gcctgatgaa gaggatttca actacacaat actatcattg tcaggactat 3300
gacctcaggc actctaaaca tatgttttgt ttggtcagca cagcgtttca aaaagtgaag 3360
ccactttata aatatttgga gattttgcag gaaaatctgg atccccaggt aaggatagca 3420
gatggttttc agttatctcc agtccacgtt cacaaaatgt gaaggtgtgg agacacttac 3480
aaagctgcct cacttctcac tgtaaacatt agctctttcc actgcctacc tggaccccag 3540
tctaggaatt aaatctgcac ctaaccaagg tcccttgtaa gaaatgtcca ttcaagcagt 3600
cattctctgg gtatataata tgattttgac taccttatct ggtgttaaga tttgaagttg 3660
gccttttatt ggactaaagg ggaactcctt taagggtctc agttagccca agtttctttt 3720
gcttatatgt taatagtttt accctctgca ttggagagag gagtgcttta ctccaagaag 3780
ctttcctcat ggttaccgtt ctctccatca tgccagcctt ctcaaccttt gcagaaatta 3840
ctagagagga tttgaatgtg ggacacaaag gtcccatttg cagttagaaa atttgtgtcc 3900
acaaggacaa gaacaaagta tgagctttaa aactccatag gaaacttgtt aatcaacaaa 3960
gaagtgttaa tgctgcaagt aatctctttt ttaaaacttt ttgaagctac ttattttcag 4020
ccaaatagga atattagaga gggactggta gtgagaatat cagctctgtt tggatggtgg 4080
aaggtctcat tttattgaga tttttaagat acatgcaaag gtttggaaat agaacctcta 4140
ggcaccctcc tcagtgtggg tgggctgaga gttaaagaca gtgtggctgc agtagcatag 4200
aggcgcctag aaattccact tgcaccgtag ggcatgctga taccatccca atagctgttg 4260
cccattgacc tctagtggtg agtttctaga atactggtcc attcatgaga tattcaagat 4320
tcaagagtat tctcacttct gggttatcag cataaactgg aatgtagtgt cagaggatac 4380
tgtggcttgt tttgtttatg tttttttttc ttattcaaga aaaaagacca aggaataaca 4440
ttctgtagtt cctaaaaata ctgacttttt tcactactat acataaaggg aaagttttat 4500
tcttttatgg aacacttcag ctgtactcat gtattaaaat aggaatgtga atgctatata 4560
ctctttttat atcaaaagtc tcaagcactt atttttattc tatgcattgt ttgtctttta 4620
cataaataaa atgtttatta gattgaataa agcaaaatac tcaggtgagc atcctgcctc 4680
ctgttcccat tcctagtagc taaa 4704
<210> 4
<211> 592
<212> PRT
<213> 智人
<400> 4
Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu
1 5 10 15
Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Asp
20 25 30
Val Glu Met Glu Ala Gln Lys Asp Glu Ile Ile Cys Pro Ser Cys Asn
35 40 45
Arg Thr Ala His Pro Leu Arg His Ile Asn Asn Asp Met Ile Val Thr
50 55 60
Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp
65 70 75 80
Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys
85 90 95
Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val
100 105 110
Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp
115 120 125
Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro
130 135 140
Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met
145 150 155 160
Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu
165 170 175
Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val
180 185 190
Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile
195 200 205
Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser
210 215 220
Thr Trp Glu Thr Gly Lys Thr Arg Lys Leu Met Glu Phe Ser Glu His
225 230 235 240
Cys Ala Ile Ile Leu Glu Asp Asp Arg Ser Asp Ile Ser Ser Thr Cys
245 250 255
Ala Asn Asn Ile Asn His Asn Thr Glu Leu Leu Pro Ile Glu Leu Asp
260 265 270
Thr Leu Val Gly Lys Gly Arg Phe Ala Glu Val Tyr Lys Ala Lys Leu
275 280 285
Lys Gln Asn Thr Ser Glu Gln Phe Glu Thr Val Ala Val Lys Ile Phe
290 295 300
Pro Tyr Glu Glu Tyr Ala Ser Trp Lys Thr Glu Lys Asp Ile Phe Ser
305 310 315 320
Asp Ile Asn Leu Lys His Glu Asn Ile Leu Gln Phe Leu Thr Ala Glu
325 330 335
Glu Arg Lys Thr Glu Leu Gly Lys Gln Tyr Trp Leu Ile Thr Ala Phe
340 345 350
His Ala Lys Gly Asn Leu Gln Glu Tyr Leu Thr Arg His Val Ile Ser
355 360 365
Trp Glu Asp Leu Arg Lys Leu Gly Ser Ser Leu Ala Arg Gly Ile Ala
370 375 380
His Leu His Ser Asp His Thr Pro Cys Gly Arg Pro Lys Met Pro Ile
385 390 395 400
Val His Arg Asp Leu Lys Ser Ser Asn Ile Leu Val Lys Asn Asp Leu
405 410 415
Thr Cys Cys Leu Cys Asp Phe Gly Leu Ser Leu Arg Leu Asp Pro Thr
420 425 430
Leu Ser Val Asp Asp Leu Ala Asn Ser Gly Gln Val Gly Thr Ala Arg
435 440 445
Tyr Met Ala Pro Glu Val Leu Glu Ser Arg Met Asn Leu Glu Asn Val
450 455 460
Glu Ser Phe Lys Gln Thr Asp Val Tyr Ser Met Ala Leu Val Leu Trp
465 470 475 480
Glu Met Thr Ser Arg Cys Asn Ala Val Gly Glu Val Lys Asp Tyr Glu
485 490 495
Pro Pro Phe Gly Ser Lys Val Arg Glu His Pro Cys Val Glu Ser Met
500 505 510
Lys Asp Asn Val Leu Arg Asp Arg Gly Arg Pro Glu Ile Pro Ser Phe
515 520 525
Trp Leu Asn His Gln Gly Ile Gln Met Val Cys Glu Thr Leu Thr Glu
530 535 540
Cys Trp Asp His Asp Pro Glu Ala Arg Leu Thr Ala Gln Cys Val Ala
545 550 555 560
Glu Arg Phe Ser Glu Leu Glu His Leu Asp Arg Leu Ser Gly Arg Ser
565 570 575
Cys Ser Glu Glu Lys Ile Pro Glu Asp Gly Ser Leu Asn Thr Thr Lys
580 585 590
<210> 5
<211> 6105
<212> DNA
<213> 智人
<400> 5
agtacagtat aaaacttcac agtgccaata ccatgaagag gagctcagac agctcttacc 60
acatgataca agagccggct ggtggaagag tggggaccag aaagagaatt tgctgaagag 120
gagaaggaaa aaaaaaacac caaaaaaaaa aataaaaaaa tccacacaca caaaaaaacc 180
tgcgcgtgag gggggaggaa aagcagggcc ttttaaaaag gcaatcacaa caacttttgc 240
tgccaggatg cccttgcttt ggctgagagg atttctgttg gcaagttgct ggattatagt 300
gaggagttcc cccaccccag gatccgaggg gcacagcgcg gcccccgact gtccgtcctg 360
tgcgctggcc gccctcccaa aggatgtacc caactctcag ccagagatgg tggaggccgt 420
caagaagcac attttaaaca tgctgcactt gaagaagaga cccgatgtca cccagccggt 480
acccaaggcg gcgcttctga acgcgatcag aaagcttcat gtgggcaaag tcggggagaa 540
cgggtatgtg gagatagagg atgacattgg aaggagggca gaaatgaatg aacttatgga 600
gcagacctcg gagatcatca cgtttgccga gtcaggaaca gccaggaaga cgctgcactt 660
cgagatttcc aaggaaggca gtgacctgtc agtggtggag cgtgcagaag tctggctctt 720
cctaaaagtc cccaaggcca acaggaccag gaccaaagtc accatccgcc tcttccagca 780
gcagaagcac ccgcagggca gcttggacac aggggaagag gccgaggaag tgggcttaaa 840
gggggagagg agtgaactgt tgctctctga aaaagtagta gacgctcgga agagcacctg 900
gcatgtcttc cctgtctcca gcagcatcca gcggttgctg gaccagggca agagctccct 960
ggacgttcgg attgcctgtg agcagtgcca ggagagtggc gccagcttgg ttctcctggg 1020
caagaagaag aagaaagaag aggaggggga agggaaaaag aagggcggag gtgaaggtgg 1080
ggcaggagca gatgaggaaa aggagcagtc gcacagacct ttcctcatgc tgcaggcccg 1140
gcagtctgaa gaccaccctc atcgccggcg tcggcggggc ttggagtgtg atggcaaggt 1200
caacatctgc tgtaagaaac agttctttgt cagtttcaag gacatcggct ggaatgactg 1260
gatcattgct ccctctggct atcatgccaa ctactgcgag ggtgagtgcc cgagccatat 1320
agcaggcacg tccgggtcct cactgtcctt ccactcaaca gtcatcaacc actaccgcat 1380
gcggggccat agcccctttg ccaacctcaa atcgtgctgt gtgcccacca agctgagacc 1440
catgtccatg ttgtactatg atgatggtca aaacatcatc aaaaaggaca ttcagaacat 1500
gatcgtggag gagtgtgggt gctcatagag ttgcccagcc cagggggaaa gggagcaaga 1560
gttgtccaga gaagacagtg gcaaaatgaa gaaattttta aggtttctga gttaaccaga 1620
aaaatagaaa ttaaaaacaa aacaaaaaaa aaaacaaaaa aaaacaaaag taaattaaaa 1680
acaaaacctg atgaaacaga tgaaggaaga tgtggaaaaa atccttagcc agggctcaga 1740
gatgaagcag tgaaagagac aggaattggg agggaaaggg agaatggtgt accctttatt 1800
tcttctgaaa tcacactgat gacatcagtt gtttaaacgg ggtattgtcc tttcccccct 1860
tgaggttccc ttgtgagcct tgaatcaacc aatctagtct gcagtagtgt ggactagaac 1920
aacccaaata gcatctagaa agccatgagt ttgaaagggc ccatcacagg cactttccta 1980
cccaattacc caggtcataa ggtatgtctg tgtgacactt atctctgtgt atatcagcat 2040
acacacacac acacacacac acacacacac acacaggcat ttccacacat tacatatata 2100
cacatactgg taaaagaaca atcgtgtgca ggtggtcaca cttccttttt ctgtaccact 2160
tttgcaacaa aacaaaacaa acaacattaa aaaattgaga acaagtatgg aaagaatgaa 2220
agatcaagga aaaaagaata ccaagttaca tttcgttaag gtgcttatga tcttagaact 2280
atgcaaccta ataggtttga aactgtttac ctgagagaga acaaaaagag agactttttt 2340
gtattggaag taatctgatt aatttttatt ttcttcaagg agagatactt gaaaggaata 2400
tgtttgtcca tctgttggat ccaaacattt ctatattttg taaatgttgt tgttgttttt 2460
tttttaatcg tttactattt gcactacaat ggtgtttgac ctgtctaatc cttatttaac 2520
aagtattttc tttggttggg ggtgggggtg gggtttaaga gctgcactta atgtgagcta 2580
taaaagaact gctacagcac acaaaatagc tatttttatt attataatta taattattat 2640
tattattttg taccttaaaa aatagacaca tacaccaaag acatttgtgt gagcctttaa 2700
acagtctgtc tgtggttggt atcattcacc atcaatgagt caggggttgg gattcaaggt 2760
tgagtagtgt ggattgtgtt caggcttaaa agacctgaga agtttggttt ttgactcctt 2820
ttacatccat gaaacaggac atttcatact ggatgtacag tagttgtaca ctgttggata 2880
tcaagttcaa tcaaattcat ggaactacat gcttgtatgt gtatatatac attgcttgtg 2940
catatgcata tctgtatgta tatatacatg tattgtacca tgtccataca cattttaagc 3000
acttcaggct gtcatttttt aatgttctta aagcaatgaa tgtttgtgtg caaaacacag 3060
tatttttaag aaggataggc tatagttttt gcttttactc tgaactaggt gggcgcattt 3120
caaaaattcg gatgggaaaa agcctggaaa ttccagtgaa tattcagcaa ggccctcttt 3180
cattgtacag ggatcaaatt tcctcctctt ttttgtgccc cctcccactt ctacaagtta 3240
tcccctgtgg ggaaaacagg atgataatca aaactctggg ctgatgtttt tccaacttag 3300
tgtctattgg aatcaatctt aaatcagaag ctttttcaga aaaataatat ttaggccaga 3360
attagagttg agtgtatttt ttaaaaatga ttaaggcttg gttgtgagaa atattacctg 3420
taccagctgg gaaaaataat gtcatcacta actaaaagat aattaatttg agagaaagtg 3480
ttaagagagg gagagtaagg aagagaacag ttaagaggag gcagaggtga gggcagtagt 3540
aaaaatctct aaaattttaa tttacagcca aaattcttca tgtgtaaatt tgtattgatt 3600
cagatgcaga aatgaaaaaa aaacaccttt gttttataaa tatcaaagta catgcttaaa 3660
gccaagtttt tatctagttt attctagtac ttagcttgcc tggaatagct aataaattat 3720
tcatgtatgt gcttttgaaa atccagagcc ctatttttac acacttgtgt gaagttggca 3780
aacattttga aaaatggaaa aaagtttcta ataattggga acaattacat taattaatat 3840
tttgtaaaat attgaagctt ttagccctat gtcaatttgt agattaaaat aaattaatta 3900
taggaaagga agataacagt gagaaaccaa acattacaaa aggtggttta gctctccttg 3960
aaaaatatac taagttggta tactataaca cttggctata tgtaggcaat gtcactactg 4020
ggcaaataca cttactgtgt tctagaggca gccctttctt atgcagaaaa tacaatacgc 4080
actgcatgag aagcttgaga gtggattcta atccaggtct gtcgaccttg gatatcatgc 4140
atgtgggaag gtgggtgtgg tgagaaaagt tttaaggcaa gagtagatgg ccatgttcaa 4200
ctttacaaaa tttcttggaa aactggcagt attttgaact gcatcttctt tggtaccgga 4260
acctgcagaa acagtgtgag aaattaagtc ctggttcact gcgcagtagc aaagatggtc 4320
aaggccatgg aaaaagcaga aatttaccaa gaaagctgat acccatgtat agttcccact 4380
catctcaaat acatctgcta tctttttaag ctaagtccta gacatatcgg ggataacatg 4440
ggggttgatt agtgaccaca gttatcagaa gcagagaaat gtaattccat attttatttg 4500
aaacttattc catattttaa ttggatattg agtgattggg ttatcaaaca cccacaaact 4560
ttaattttgt taaatttata tggctttgaa atagaagtat aagttgctac cattttttga 4620
taacattgaa agatagtatt ttaccatctt taatcatctt ggaaaataca agtcctgtga 4680
acaaccactc tttcacctag cagcatgagg ccaaaagtaa aggctttaaa ttataacata 4740
tgggattctt agtagtatgt ttttttcttg aaactcagtg gctctatcta accttactat 4800
ctcctcactc tttctctaag actaaactct aggctcttaa aaatctgccc acaccaatct 4860
tagaagctct gaaaagaatt tgtctttaaa tatcttttaa tagtaacatg tattttatgg 4920
accaaattga cattttcgac tattttttcc aaaaaagtca ggtgaatttc agcacactga 4980
gttgggaatt tcttatccca gaagaccaac caatttcata tttatttaag attgattcca 5040
tactccgttt tcaaggagaa tccctgcagt ctccttaaag gtagaacaaa tactttctat 5100
ttttttttca ccattgtggg attggacttt aagaggtgac tctaaaaaaa cagagaacaa 5160
atatgtctca gttgtattaa gcacggaccc atattatcat attcacttaa aaaaatgatt 5220
tcctgtgcac cttttggcaa cttctctttt caatgtaggg aaaaacttag tcaccctgaa 5280
aacccacaaa ataaataaaa cttgtagatg tgggcagaag gtttgggggt ggacattgta 5340
tgtgtttaaa ttaaaccctg tatcactgag aagctgttgt atgggtcaga gaaaatgaat 5400
gcttagaagc tgttcacatc ttcaagagca gaagcaaacc acatgtctca gctatattat 5460
tatttatttt ttatgcataa agtgaatcat ttcttctgta ttaatttcca aagggtttta 5520
ccctctattt aaatgctttg aaaaacagtg cattgacaat gggttgatat ttttctttaa 5580
aagaaaaata taattatgaa agccaagata atctgaagcc tgttttattt taaaactttt 5640
tatgttctgt ggttgatgtt gtttgtttgt ttgtttctat tttgttggtt ttttactttg 5700
ttttttgttt tgttttgttt tgttttgcat actacatgca gttctttaac caatgtctgt 5760
ttggctaatg taattaaagt tgttaattta tatgagtgca tttcaactat gtcaatggtt 5820
tcttaatatt tattgtgtag aagtactggt aattttttta tttacaatat gtttaaagag 5880
ataacagttt gatatgtttt catgtgttta tagcagaagt tatttatttc tatggcattc 5940
cagcggatat tttggtgttt gcgaggcatg cagtcaatat tttgtacagt tagtggacag 6000
tattcagcaa cgcctgatag cttctttggc cttatgttaa ataaaaagac ctgtttggga 6060
tgtaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaa 6105
<210> 6
<211> 426
<212> PRT
<213> 智人
<400> 6
Met Pro Leu Leu Trp Leu Arg Gly Phe Leu Leu Ala Ser Cys Trp Ile
1 5 10 15
Ile Val Arg Ser Ser Pro Thr Pro Gly Ser Glu Gly His Ser Ala Ala
20 25 30
Pro Asp Cys Pro Ser Cys Ala Leu Ala Ala Leu Pro Lys Asp Val Pro
35 40 45
Asn Ser Gln Pro Glu Met Val Glu Ala Val Lys Lys His Ile Leu Asn
50 55 60
Met Leu His Leu Lys Lys Arg Pro Asp Val Thr Gln Pro Val Pro Lys
65 70 75 80
Ala Ala Leu Leu Asn Ala Ile Arg Lys Leu His Val Gly Lys Val Gly
85 90 95
Glu Asn Gly Tyr Val Glu Ile Glu Asp Asp Ile Gly Arg Arg Ala Glu
100 105 110
Met Asn Glu Leu Met Glu Gln Thr Ser Glu Ile Ile Thr Phe Ala Glu
115 120 125
Ser Gly Thr Ala Arg Lys Thr Leu His Phe Glu Ile Ser Lys Glu Gly
130 135 140
Ser Asp Leu Ser Val Val Glu Arg Ala Glu Val Trp Leu Phe Leu Lys
145 150 155 160
Val Pro Lys Ala Asn Arg Thr Arg Thr Lys Val Thr Ile Arg Leu Phe
165 170 175
Gln Gln Gln Lys His Pro Gln Gly Ser Leu Asp Thr Gly Glu Glu Ala
180 185 190
Glu Glu Val Gly Leu Lys Gly Glu Arg Ser Glu Leu Leu Leu Ser Glu
195 200 205
Lys Val Val Asp Ala Arg Lys Ser Thr Trp His Val Phe Pro Val Ser
210 215 220
Ser Ser Ile Gln Arg Leu Leu Asp Gln Gly Lys Ser Ser Leu Asp Val
225 230 235 240
Arg Ile Ala Cys Glu Gln Cys Gln Glu Ser Gly Ala Ser Leu Val Leu
245 250 255
Leu Gly Lys Lys Lys Lys Lys Glu Glu Glu Gly Glu Gly Lys Lys Lys
260 265 270
Gly Gly Gly Glu Gly Gly Ala Gly Ala Asp Glu Glu Lys Glu Gln Ser
275 280 285
His Arg Pro Phe Leu Met Leu Gln Ala Arg Gln Ser Glu Asp His Pro
290 295 300
His Arg Arg Arg Arg Arg Gly Leu Glu Cys Asp Gly Lys Val Asn Ile
305 310 315 320
Cys Cys Lys Lys Gln Phe Phe Val Ser Phe Lys Asp Ile Gly Trp Asn
325 330 335
Asp Trp Ile Ile Ala Pro Ser Gly Tyr His Ala Asn Tyr Cys Glu Gly
340 345 350
Glu Cys Pro Ser His Ile Ala Gly Thr Ser Gly Ser Ser Leu Ser Phe
355 360 365
His Ser Thr Val Ile Asn His Tyr Arg Met Arg Gly His Ser Pro Phe
370 375 380
Ala Asn Leu Lys Ser Cys Cys Val Pro Thr Lys Leu Arg Pro Met Ser
385 390 395 400
Met Leu Tyr Tyr Asp Asp Gly Gln Asn Ile Ile Lys Lys Asp Ile Gln
405 410 415
Asn Met Ile Val Glu Glu Cys Gly Cys Ser
420 425
<210> 7
<211> 2988
<212> DNA
<213> 智人
<400> 7
gcaggagggc ccagcgacgc cgccgcgcca gctcccaggg cccggccccc cccggcgctc 60
acgctctcgg ggcggactcc cggccctccg cgccctctcg cgcggcgatg gccccactcg 120
gatacttctt actcctctgc agcctgaagc aggctctggg cagctacccg atctggtggt 180
cgctggctgt tgggccacag tattcctccc tgggctcgca gcccatcctg tgtgccagca 240
tcccgggcct ggtccccaag cagctccgct tctgcaggaa ctacgtggag atcatgccca 300
gcgtggccga gggcatcaag attggcatcc aggagtgcca gcaccagttc cgcggccgcc 360
ggtggaactg caccaccgtc cacgacagcc tggccatctt cgggcccgtg ctggacaaag 420
ctaccaggga gtcggccttt gtccacgcca ttgcctcagc cggtgtggcc tttgcagtga 480
cacgctcatg tgcagaaggc acggccgcca tctgtggctg cagcagccgc caccagggct 540
caccaggcaa gggctggaag tggggtggct gtagcgagga catcgagttt ggtgggatgg 600
tgtctcggga gttcgccgac gcccgggaga accggccaga tgcccgctca gccatgaacc 660
gccacaacaa cgaggctggg cgccaggcca tcgccagcca catgcacctc aagtgcaagt 720
gccacgggct gtcgggcagc tgcgaggtga agacatgctg gtggtcgcaa cccgacttcc 780
gcgccatcgg tgacttcctc aaggacaagt acgacagcgc ctcggagatg gtggtggaga 840
agcaccggga gtcccgcggc tgggtggaga ccctgcggcc gcgctacacc tacttcaagg 900
tgcccacgga gcgcgacctg gtctactacg aggcctcgcc caacttctgc gagcccaacc 960
ctgagacggg ctccttcggc acgcgcgacc gcacctgcaa cgtcagctcg cacggcatcg 1020
acggctgcga cctgctgtgc tgcggccgcg gccacaacgc gcgagcggag cggcgccggg 1080
agaagtgccg ctgcgtgttc cactggtgct gctacgtcag ctgccaggag tgcacgcgcg 1140
tctacgacgt gcacacctgc aagtaggcac cggccgcggc tccccctgga cggggcgggc 1200
cctgcctgag ggtgggcttt tccctgggtg gagcaggact cccacctaaa cggggcagta 1260
ctcctccctg ggggcgggac tcctccctgg gggtggggct cctacctggg ggcagaactc 1320
ctacctgaag gcagggctcc tccctggagc tagtgtctcc tctctggtgg ctgggctgct 1380
cctgaatgag gcggagctcc aggatgggga ggggctctgc gttggcttct ccctggggac 1440
ggggctcccc tggacagagg cggggctaca gattgggcgg ggcttctctt gggtgggaca 1500
gggcttctcc tgcgggggcg aggcccctcc cagtaagggc gtggctctgg gtgggcgggg 1560
cactaggtag gcttctacct gcaggcgggg ctcctcctga aggaggcggg gctctaggat 1620
ggggcacggc tctggggtag gctgctccct gagggcggag cgcctcctta ggagtggggt 1680
tttatggtgg atgaggcttc ttcctggatg gggcagagct tctcctgacc agggcaaggc 1740
cccttccacg ggggctgtgg ctctgggtgg gcgtggcctg cataggctcc ttcctgtggg 1800
tggggcttct ctgggaccag gctccaatgg ggcggggctt ctctccgcgg gtgggactct 1860
tccctgggaa ccgccctcct gattaaggcg tggcttctgc aggaatcccg gctccagagc 1920
aggaaattca gcccaccagc cacctcatcc ccaaccccct gtaaggttcc atccacccct 1980
gcgtcgagct gggaaggttc catgaagcga gtcgggtccc caacccgtgc ccctgggatc 2040
cgagggcccc tctccaagcg cctggctttg gaatgctcca ggcgcgccga cgcctgtgcc 2100
accccttcct cagcctgggg tttgaccacc cacctgacca ggggccctac ctggggaaag 2160
cctgaagggc ctcccagccc ccaaccccaa gaccaagctt agtcctggga gaggacaggg 2220
acttcgcaga ggcaagcgac cgaggccctc ccaaagaggc ccgccctgcc cgggctccca 2280
caccgtcagg tactcctgcc agggaactgg cctgctgcgc cccaggcccc gcccgtctct 2340
gctctgctca gctgcgcccc cttctttgca gctgcccagc ccctcctccc tgccctcggg 2400
tctccccacc tgcactccat ccagctacag gagagataga agcctctcgt cccgtccctc 2460
cctttcctcc gcctgtccac agccccttaa gggaaaggta ggaagagagg tccagccccc 2520
caggctgccc agagctgctg gtctcatttg ggggcgttcg ggaggtttgg ggggcatcaa 2580
ccccccgact gtgctgctcg cgaaggtccc acagccctga gatgggccgg cccccttcct 2640
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Leu Gly Ser Tyr Pro Ile Trp Trp Ser Leu Ala Val Gly Pro Gln Tyr
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Ser Ser Leu Gly Ser Gln Pro Ile Leu Cys Ala Ser Ile Pro Gly Leu
35 40 45
Val Pro Lys Gln Leu Arg Phe Cys Arg Asn Tyr Val Glu Ile Met Pro
50 55 60
Ser Val Ala Glu Gly Ile Lys Ile Gly Ile Gln Glu Cys Gln His Gln
65 70 75 80
Phe Arg Gly Arg Arg Trp Asn Cys Thr Thr Val His Asp Ser Leu Ala
85 90 95
Ile Phe Gly Pro Val Leu Asp Lys Ala Thr Arg Glu Ser Ala Phe Val
100 105 110
His Ala Ile Ala Ser Ala Gly Val Ala Phe Ala Val Thr Arg Ser Cys
115 120 125
Ala Glu Gly Thr Ala Ala Ile Cys Gly Cys Ser Ser Arg His Gln Gly
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Ser Pro Gly Lys Gly Trp Lys Trp Gly Gly Cys Ser Glu Asp Ile Glu
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Phe Gly Gly Met Val Ser Arg Glu Phe Ala Asp Ala Arg Glu Asn Arg
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Pro Asp Ala Arg Ser Ala Met Asn Arg His Asn Asn Glu Ala Gly Arg
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Gln Ala Ile Ala Ser His Met His Leu Lys Cys Lys Cys His Gly Leu
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Ser Gly Ser Cys Glu Val Lys Thr Cys Trp Trp Ser Gln Pro Asp Phe
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Arg Ala Ile Gly Asp Phe Leu Lys Asp Lys Tyr Asp Ser Ala Ser Glu
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Met Val Val Glu Lys His Arg Glu Ser Arg Gly Trp Val Glu Thr Leu
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Arg Pro Arg Tyr Thr Tyr Phe Lys Val Pro Thr Glu Arg Asp Leu Val
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Tyr Tyr Glu Ala Ser Pro Asn Phe Cys Glu Pro Asn Pro Glu Thr Gly
275 280 285
Ser Phe Gly Thr Arg Asp Arg Thr Cys Asn Val Ser Ser His Gly Ile
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Asp Gly Cys Asp Leu Leu Cys Cys Gly Arg Gly His Asn Ala Arg Ala
305 310 315 320
Glu Arg Arg Arg Glu Lys Cys Arg Cys Val Phe His Trp Cys Cys Tyr
325 330 335
Val Ser Cys Gln Glu Cys Thr Arg Val Tyr Asp Val His Thr Cys Lys
340 345 350
Claims (78)
1.一种产生形成性胚胎干细胞(ESC)的制备方法,所述方法包括:
(i)获得生殖细胞群,以及
(ii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基中培养生殖细胞群,
从而产生形成性ESC。
2.权利要求1的方法,其中所述生殖细胞群包括囊胚。
3.权利要求1或权利要求2的方法,其中所述生殖细胞群获自受试者。
4.权利要求3的方法,其中所述受试者选自人、啮齿类动物和有蹄类动物。
5.权利要求1-4中任一项的方法,其中所述FGF激活剂选自蛋白质、核酸、小分子及其组合。
6.权利要求5的方法,其中所述FGF激活剂是FGF蛋白。
7.权利要求1-6中任一项的方法,其中所述TGF-β激活剂选自蛋白质、核酸、小分子及其组合。
8.权利要求7的方法,其中所述TGF-β激活剂是TGF-β蛋白。
9.权利要求7的方法,其中所述TGF-β激活剂是激活素A蛋白。
10.权利要求1-9中任一项的方法,其中所述WNT激活剂选自蛋白质、核酸、小分子及其组合。
11.权利要求10的方法,其中所述WNT激活剂是WNT蛋白。
12.权利要求1-11中任一项的方法,其中所述WNT激活剂是GSK3抑制剂和/或MEK抑制剂。
13.权利要求12的方法,其中所述GSK3抑制剂是CHIR99021。
14.权利要求1-13中任一项的方法,其中步骤(ii)进行1至8天。
15.权利要求1-14中任一项的方法,其中在步骤(ii)之前,将所述生殖细胞群在包含至少一种额外因子的培养基中培养。
16.权利要求1-15中任一项的方法,其中步骤(ii)中的培养基还包含至少一种额外因子。
17.权利要求16的方法,其中所述至少一种额外因子是MEK抑制剂、胎牛血清(FBS)、白血病抑制因子(LIF)、JNK抑制剂或其组合。
18.权利要求17的方法,其中所述MEK抑制剂是PD0325901。
19.权利要求17的方法,其中所述JNK抑制剂是SP600125。
20.权利要求1-19中任一项的方法,其中在至少一种分化因子的存在下培养步骤(ii)中产生的形成性ESC,其中所述至少一种分化因子选自生长因子、WNT抑制剂、JNK抑制剂和TGF-β抑制剂。
21.权利要求20的方法,其中所述生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。
22.权利要求20或权利要求21的方法,其中所述WNT抑制剂是IWP2。
23.权利要求20-22中任一项的方法,其中所述TGF-β抑制剂是SB431542。
24.权利要求20-23中任一项的方法,其中所述JNK抑制剂是SP600125。
25.一种用于产生形成性诱导多能干细胞(iPSC)的方法,所述方法包括:
(i)获得体细胞群,
(ii)在包含重编程剂的第一培养基中培养体细胞群,所述重编程剂调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达,和
(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养体细胞群,
从而产生形成性iPSC。
26.权利要求25的方法,其中所述体细胞群包括胚胎成纤维细胞。
27.权利要求25或权利要求26的方法,其中所述体细胞群获自受试者。
28.权利要求25的方法,其中所述受试者选自灵长类动物、啮齿类动物和有蹄类动物。
29.权利要求25-28中任一项的方法,其中所述重编程剂包括核酸。
30.权利要求29的方法,其中所述核酸编码重编程基因。
31.权利要求29的方法,其中所述核酸编码靶向重编程基因的干扰RNA。
32.权利要求29-31中任一项的方法,其中所述核酸包含在载体中。
33.权利要求32的方法,其中所述载体是附加型载体。
34.权利要求25-33中任一项的方法,其中所述FGF激活剂选自蛋白质、核酸、小分子及其组合。
35.权利要求34的方法,其中所述FGF激活剂是FGF蛋白。
36.权利要求25-35中任一项的方法,其中所述TGF-β激活剂选自蛋白质、核酸、小分子及其组合。
37.权利要求36的方法,其中所述TGF-β激活剂是TGF-β蛋白。
38.权利要求36的方法,其中所述TGF-β激活剂是激活素A蛋白。
39.权利要求25-38中任一项的方法,其中所述WNT激活剂选自蛋白质、核酸、小分子及其组合。
40.权利要求39的方法,其中所述WNT激活剂是WNT蛋白。
41.权利要求25-40中任一项的方法,其中所述WNT激活剂是GSK3抑制剂。
42.权利要求41的方法,其中所述GSK3抑制剂是CHIR99021。
43.权利要求24-42中任一项的方法,其中步骤(ii)进行1至6天。
44.权利要求24-43中任一项的方法,其中步骤(iii)进行1至8天。
45.权利要求25-44中任一项的方法,其中在至少一种分化因子存在的情况下培养在步骤(iii)中产生的形成性iPSC。
46.权利要求45的方法,其中所述至少一种分化因子选自生长因子、WNT抑制剂、JNK抑制剂和TGF-β抑制剂。
47.权利要求46的方法,其中所述生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。
48.权利要求46或权利要求47的方法,其中所述WNT抑制剂是IWP2。
49.权利要求46-48中任一项的方法,其中所述TGF-β抑制剂是SB431542。
50.权利要求46-48中任一项的方法,其中所述JNK抑制剂是SP600125。
51.一种体外培养系统,包含:
(a)细胞群,和
(b)包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基。
52.权利要求50的体外培养系统,进一步包含调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达的重编程剂。
53.权利要求51或权利要求52的体外培养系统,其中所述细胞群包括生殖细胞或体细胞。
54.权利要求51-53中任一项的体外培养系统,其中所述细胞群包括囊胚或胚胎成纤维细胞。
55.权利要求51-54中任一项的体外培养系统,其中生殖细胞群获自受试者。
56.权利要求55的体外培养系统,其中所述受试者选自灵长类动物、啮齿类动物和有蹄类动物。
57.权利要求51-56中任一项的体外培养系统,其中所述FGF激活剂选自蛋白质、核酸、小分子及其组合。
58.权利要求57的体外培养系统,其中所述FGF激活剂是FGF蛋白。
59.权利要求51-58中任一项的体外培养系统,其中所述TGF-β激活剂选自蛋白质、核酸、小分子及其组合。
60.权利要求59的体外培养系统,其中所述TGF-β激活剂是TGF-β蛋白。
61.权利要求59的体外培养系统,其中所述TGF-β激活剂是激活素A蛋白。
62.权利要求51-61中任一项的体外培养系统,其中所述WNT激活剂选自蛋白质、核酸、小分子及其组合。
63.权利要求62的体外培养系统,其中所述WNT激活剂是WNT蛋白。
64.权利要求51-63中任一项的体外培养系统,其中所述WNT激活剂是GSK3抑制剂。
65.权利要求64的体外培养系统,其中所述GSK3抑制剂是CHIR99021。
66.权利要求51-65中任一项的体外培养系统,其中所述培养基还包含至少一种额外因子。
67.权利要求66的体外培养系统,其中所述至少一种额外因子是MEK抑制剂、胎牛血清(FBS)、白血病抑制因子(LIF)、JNK抑制剂或其组合。
68.权利要求67的体外培养系统,其中所述MEK抑制剂是PD0325901。
69.权利要求67的体外培养系统,其中所述JNK抑制剂是SP600125。
70.权利要求42-69中任一项的体外培养系统,其中所述培养基还包含至少一种分化因子。
71.权利要求70的体外培养系统,其中所述至少一种分化因子选自生长因子、WNT抑制剂和TGF-β抑制剂。
72.权利要求71的体外培养系统,其中所述生长因子是成纤维细胞生长因子(FGF)、头蛋白或其组合。
73.权利要求71或权利要求72的体外培养系统,其中所述WNT抑制剂是IWP2。
74.权利要求71-73中任一项的体外培养系统,其中所述TGF-β抑制剂是SB431542。
75.一种用于产生形成性胚胎干细胞(ESC)的方法,所述方法包括:
(i)从小鼠获得生殖细胞群,
(ii)在包含MEK抑制剂的第一培养基中培养生殖细胞群,和
(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性小鼠ESC。
76.一种用于产生形成性胚胎干细胞(ESC)的方法,所述方法包括:
(i)从马获得生殖细胞群,
(ii)首先在包含胎牛血清(FBS)、成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的培养基中培养生殖细胞群,和
(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性马ESC。
77.一种用于产生形成性胚胎干细胞(ESC)的方法,所述方法包括:
(i)从猪获得生殖细胞群,
(ii)首先在包含胎牛血清(FBS)、成纤维细胞生长因子(FGF)激活剂、白血病抑制因子(LIF)激活剂、转化生长因子β(TGF-fβ)激活剂和WNT激活剂的培养基中培养生殖细胞群,和
(iii)在包含成纤维细胞生长因子(FGF)激活剂、白血病抑制因子(LIF)激活剂、转化生长因子β(TGF-fβ)激活剂和WNT激活剂的第二培养基中培养生殖细胞群,从而产生形成性猪ESC。
78.一种用于产生形成性诱导多能干细胞(iPSC)的方法,所述方法包括:
(i)从人获得体细胞群,
(ii)在包含重编程剂的第一培养基中培养体细胞群,所述重编程剂调节选自OCT3/4、p53、SOX2、KLF4、L-MYC和LIN28的至少一种重编程基因的表达,和
(iii)在包含成纤维细胞生长因子(FGF)激活剂、转化生长因子β(TGF-β)激活剂、JNK抑制剂和WNT激活剂的第二培养基中培养体细胞群,
从而产生形成性人iPSC。
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