CN114903992A - 转录因子bcl11a在制备施万细胞调控药物中的应用 - Google Patents
转录因子bcl11a在制备施万细胞调控药物中的应用 Download PDFInfo
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- CN114903992A CN114903992A CN202210403635.0A CN202210403635A CN114903992A CN 114903992 A CN114903992 A CN 114903992A CN 202210403635 A CN202210403635 A CN 202210403635A CN 114903992 A CN114903992 A CN 114903992A
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Abstract
本发明提供了转录因子BCL11A在制备施万细胞调控药物中的应用。本发明首次揭示敲降Bcl11a基因表达能够抑制施万细胞的增殖和迁移，研究结果表明转录因子BCL11A能调节施万细胞的增殖和迁移功能。BCL11A可以作为药物设计靶点，用于治疗施万细胞过度生长相关疾病。
Description
技术领域
本发明涉及生物医药领域，特别涉及BAF Chromatin Remodeling ComplexSubunit BCL11A(BCL11A)在制备施万细胞调控药物中的应用。
背景技术
施万细胞是周围神经系统特有的胶质细胞，除为神经元细胞提供物理支撑，还具有分隔绝缘、营养分泌、物质运输、化学物质摄取、髓鞘形成等重要功能，参与神经系统的发育和再生。周围神经损伤后，施万细胞经历重编程和去分化，大量增殖并迁移至受损神经处，吞噬和消化轴突和髓鞘碎片，并形成Büngner带，引导再生轴突向远侧端生长。损伤修复后期，高度去分化的施万细胞再次经历分化过程，重新形成髓鞘，包绕神经元新生轴突，加速神经冲动沿神经纤维传导的速度，并保证神经兴奋的定向传导，以实现周围神经的运动和感觉功能恢复。
施万细胞的高度可塑性为受损神经的再生提供再生的良好微环境。但过度增殖迁移的施万细胞可能造成受损神经处的施万细胞无法正常分化形成髓鞘，导致新生的轴突无髓鞘包绕，影响神经信号的传导和受损神经的功能恢复。此外，过度生长的施万细胞也可能导致神经鞘瘤的发生。探寻合适途径调控施万细胞的生长具有重要的科学意义和临床价值。
转录因子是一类可识别并结合基因启动子区域特定DNA序列，调控基因转录，进而使靶基因以特定的强度在特定的时间与空间表达的重要蛋白质分子。转录因子通过上调或下调其靶基因的表达，调节细胞凋亡、增殖、分化等生物学过程，参与调控多种生理病理过程。转录因子可以调控多个靶基因，因此，相较于调控单个基因的表达，调控转录因子的表达可起到更为显著和高效的生物学效应。
转录因子BCL11A是C2H2型锌指蛋白，是B细胞恶性肿瘤的致癌因子，在非小细胞肺癌、三阴乳腺癌、宫颈癌、卵巢癌、前列腺癌等多种实体肿瘤中均表达异常。
发明内容
本发明联合使用高通量测序数据和生物信息学分析挖掘大鼠坐骨神经损伤后差异表达的关键转录因子BCL11A，首次揭示了BCL11A与施万细胞的增殖和迁移之间的关系，证明了敲降Bcl11a基因能抑制施万细胞的增殖和迁移。
本发明具体技术方案如下：
转录因子BCL11A在制备施万细胞调控药物中的应用。
所述转录因子在人、鼠中高度保守，人和鼠的核酸序列同源性为94.83％，氨基酸序列同源性为99.53％。虽然本发明以大鼠源转录因子BCL11A(氨基酸序列如SEQ ID NO:1所示，核苷酸序列如SEQ ID NO:2所示)作为研究对象，但是不应视为对本发明的限制。
本发明所述转录因子具有与SEQ ID NO:1所示序列95％及以上同源的氨基酸序列，优选BCL11A为人或鼠源转录因子BCL11A。
本发明所述的应用，BCL11A作为药物设计靶点设计抑制BCL11A表达的药物，抑制施万细胞的增殖和迁移。抑制BCL11A表达的药物可以为转录因子BCL11A的蛋白类抑制剂、核酸适配体和/或PF4编码基因的干扰RNA、gRNA、microRNA、小分子化合物抑制剂中的一种或几种。本发明一个示例，所述抑制BCL11A表达的药物是Bcl11a基因的小干扰RNA(siRNA)。
小干扰RNA(siRNA)是化学修饰的专门针对细胞中特异性的靶基因的抑制剂，在本发明中根据靶基因Bcl11a目的片段设计了小干扰RNA，小干扰RNA的靶序列如SEQ ID NO:2所示。
本发明所述施万细胞调控药物包括神经损伤后施万细胞大量增殖引发施万细胞的分化障碍以或施万细胞过度生长疾病如神经鞘瘤。
本发明所述的抑制BCL11A表达的药物为治疗施万细胞过度生长的药物。所述施万细胞过度生长疾病包括由于神经损伤后施万细胞难以正常分化形成髓鞘导致的运动和感觉功能恢复受阻或神经鞘瘤。
施万细胞是具有高度可塑性的周围神经胶质细胞。成熟施万细胞所经历的增殖和迁移过程对神经损伤后微环境的重塑和神经的再生具有重要作用，但施万细胞的增殖和迁移应受到精准的调控，防止由于施万细胞过度生长导致的髓鞘形成障碍和神经鞘瘤等周围神经相关疾病。神经营养因子、细胞因子、生长因子、细胞外基质组分等多种因子可以调控施万细胞的增殖和迁移，影响周围神经相关疾病的病程发展和预后。改变转录因子的表达可以同时影响该转录因子的多个下游靶基因，是调控细胞表型的有效途径，也是控制施万细胞过度生长的有效手段。
为了评价BCL11A在施万细胞中的生物学功能，本发明检测了大鼠周围神经损伤后，Bcl11a基因和BCL11A蛋白的表达情况，发现BCL11A在神经损伤后表达上调且与施万细胞标志物S100β共定位，表明施万细胞表达BCL11A(图1)。培养原代大鼠施万细胞，转染针对Bcl11a的siRNA片段敲降Bcl11a的表达，EdU增殖实验和Ki67免疫荧光染色结果表明抑制BCL11A表达降低了施万细胞的增殖率(图2)。划痕愈合实验、Transwell迁移实验和活细胞工作站结果表明抑制BCL11A表达减缓了施万细胞的运动和迁移速度(图3)。进一步评估BCL11A在体内的生物学效应，在大鼠坐骨神经夹伤模型的损伤部位局部注射动物实验用Bcl11a的siRNA片段。与注射对照siRNA的大鼠相比，注射Bcl11a的siRNA干扰片段后，大鼠受损神经处增殖的施万细胞数目较少，且施万细胞从损伤两侧迁移的距离较短，表明降低大鼠体内BCL11A的表达可抑制施万细胞的增殖和迁移(图4)。生物信息学预测结果表明BCL11A可能靶向调控卷曲相关蛋白基因(frizzled related protein,Frzb)、胰岛因子1(insulin gene enhancer protein ISL-1,Isl1)、核受体亚家族2基因(nuclear receptorsubfamily 2 group F member 2,Nr2f2)和FMS样酪氨酸激酶3(Fms related receptortyrosine kinase 3,Flt3)(图5)。
本发明所述BCL11A可以直接作为药物的靶点设计抑制其表达的药物(抑制剂)，通过与药物的相互作用，抑制机体BCL11A的表达，进而发挥调节施万细胞功能的作用。
本发明的优点：本发明研究结果表明，可通过降低BCL11A的表达抑制施万细胞的增殖和迁移，可以用于治疗神经损伤后施万细胞难以正常分化形成髓鞘导致的运动和感觉功能恢复受阻以及神经鞘瘤等由于施万细胞过度生长导致的周围神经系统相关疾病的治疗。由于BCL11A是转录因子，调控BCL11A的表达可以更为及时和有效地调控施万细胞的表型，进而发挥其生物学作用。
附图说明
图1为大鼠坐骨神经损伤后BCL11A的表达。(图1A为大鼠坐骨神经损伤后0天、1天和4天，测序结果中Bcl11a基因的表达趋势；图1B为RT-PCR检测损伤段Bcl11a基因的表达变化情况；图1C为坐骨神经损伤后，BCL11A蛋白的表达和定位，红色表示BCL11A，绿色表示S100β，蓝色表示细胞核，左边图片比例尺为1000μm，右边图片为左边图片中白色方框区域的放大图，比例尺为50μm)。
图2为BCL11A对施万细胞增殖的影响。(图2A为施万细胞中Bcl11a和Gapdh的Realtime-PCR扩增曲线；图2B为施万细胞中si-Bcl11a敲降效率；图2C为siRNA对照和si-Bcl11a转染施万细胞代表性EdU增殖图像，红色表示EdU染色，蓝色表示细胞核，比例尺为50μm；图2D为施万细胞EdU增殖速率归一化统计；图2E为siRNA对照和si-Bcl11a转染施万细胞后Ki67的表达，红色表示Ki67，蓝色表示细胞核，比例尺为50μm；图2F为施万细胞Ki67阳性数目归一化统计)。
图3为BCL11A对施万细胞迁移的影响。(图3A为siRNA对照和si-Bcl11a转染施万细胞后代表性划痕愈合图像，比例尺为100μm；图3B为相对空白面积归一化统计；图3C为siRNA对照和si-Bcl11a转染施万细胞后在Transwell中迁移情况代表图像，比例尺为50μm；图3D为细胞迁移能力归一化统计；图3E为siRNA对照和si-Bcl11a转染施万细胞的平均运动轨迹；图3F为siRNA对照和si-Bcl11a转染施万细胞的运动速率)。
图4为大鼠体内抑制BCL11A表达对受损坐骨神经的影响。(图4A为大鼠损伤1天和4天后，注射siRNA对照和si-Bcl11a组，施万细胞增殖迁移情况，白色表示EdU，红色表示S100β，蓝色表示细胞核，比例尺为100μm，下方图片为图片中白色方框区域的放大图，比例尺为50μm；图4B为大鼠损伤1天和4天后，注射siRNA对照和si-Bcl11a组，损伤轴突再生情况，绿色表示SCG10，蓝色表示细胞核，比例尺为1000μm；图4C为施万细胞增殖率归一化统计；图4D为轴突再生长度归一化统计)。
图5为BCL11A的潜在靶基因。(图5A为生物信息学软件JASPAR、AnimalTF、St、TFtarget和TargetScan预测的BCL11A靶基因的交集；图5B为交集中BCL11A四个潜在靶基因Frzb、Isl1、Nr2f2和Flt3；图5C为BCL11A调控Frzb、Isl1、Nr2f2和Flt3影响施万细胞表型的潜在分子机制)。
具体实施方式
以下通过实施例说明本发明的具体步骤，但不受实施例限制。
在本发明中所使用的术语，除非另有说明，一般具有本领域普通技术人员通常理解的含义。
下面结合具体实施例并参照数据进一步详细描述本发明。应理解，该实施例只是为了举例说明本发明，而非以任何方式限制本发明的范围。
在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
下面结合具体实施例对本发明进一步说明。
实施例1BCL11A的抑制剂和抑制剂对照均由广州市锐博生物科技有限公司合成。抑制剂siRNA-Bcl11a靶序列为：5’CTTAGAAAGCGAACACGGA3’(SEQ ID NO:3)。
抑制剂对照为无意义随机序列。
转染试剂lipofectamine RNAimax由Invitrogen公司生产。
实施例2施万细胞的培养、纯化和转染
取新生1天SD大鼠，眼科剪断头处死后，用眼科镊轻轻拨开大腿处皮肤，分离肌肉，暴露股骨后外侧肌间隙，分离坐骨神经，剪碎后使用胶原酶和胰酶消化，过滤离心后弃去上清，重悬沉淀，并种于预先用PLL包被好的培养皿中。37℃培养箱培养24小时后换成含10mM阿糖胞苷的完全培养基。继续培养36至48小时后，换成含有2μM Forskolin和10ng/mLHRG的完全培养基。培养48小时后，使用Thy 1.1和rabbit complement 1:3混合液进行细胞纯化，纯化后继续使用含有2μM forskolin和10ng/mL HRG的完全培养基进行细胞培养以用于后续实验。
化学合成的BCL11A抑制剂和抑制剂对照物如实施例1所示(广州市锐博生物科技有限公司合成)，转染使用Lipofectamine RNAimax试剂(Invitrogen,Carlsbad,CA,USA)，根据说明书操作。
实施例3real-time RT-PCR(qRT-PCR)
取实施例2转染siRNA-Bcl11a的施万细胞，提取RNA，采用Oligo dT primer(Invitrogen)进行逆转录。Real-time RT-PCR采用SYBR Green Premix Ex Taq(TaKaRaBio,Inc.)在Applied Biosystems Stepone real-time PCR System上进行操作。BCL11A特异性引物序由一对qRT-PCR引物组成，序列如下：
Bcl11a(forward)：5’ACTTAGAGAGCTGGCAGGGA3’(SEQ ID NO:4)。
Bcl11a(reverse)：5’GCTACCTGGCTGGAATGGTT 3’(SEQ ID NO:5)。
qRT-PCR反应程序：95℃预变性2min；40个PCR循环(95℃，5s；60℃，10s)，在每个循环的延伸阶段收集荧光值；PCR扩增反应结束后，进行产物的溶解曲线分析，以确保PCR产物的质量。CT设为反应达到域值时的循环数，使用Gapdh作为内参，ΔΔCT法计算Bcl11a的相对表达量。
结果如图2B所示，结果显示转染BCL11A抑制剂(si-Bcl11a)的施万细胞中Bcl11a的相对表达量明显低于抑制剂对照(si-Ctr)组，结果表明本发明设计的BCL11A抑制剂能够抑制BCL11A的表达。
实施例4细胞EdU增殖试验
取实施例2的施万细胞重悬于完全培养基并接种到PLL包被的96孔板上。加入100μM EdU，EdU处理12小时后使用4％多聚甲醛固定。根据Cell-Light EdU DNA CellProliferation Kit(广州市锐博生物科技有限公司)说明书进行操作。分别统计EdU阳性细胞和总细胞数，计算EdU阳性细胞数与总细胞数的比值，确定细胞增殖速率。
图2C为高倍显微镜下细胞EdU增殖图像(比例尺为50μm)，图2D为转染BCL11A抑制剂的施万细胞的增殖速率，结果显示，转染BCL11A抑制剂的施万细胞的增殖速率低于抑制剂对照组，表明BCL11A抑制剂能降低施万细胞的增殖速率。
实施例5细胞Ki67染色实验
取实施例2的施万细胞，使用4％多聚甲醛固定，加入免疫染色封闭液孵育后，加入一抗4℃孵育过夜，PBS清洗后，避光滴加二抗室温孵育2小时，加入DAPI封片液，封面后拍照观察Ki67阳性细胞数目，通过计算增殖蛋白Ki67阳性细胞数目检测施万细胞的增殖情况。
图2E为高倍显微镜下细胞Ki67染色图像(比例尺为50μm)，图2F为转染BCL11A抑制剂的施万细胞中Ki67阳性细胞相对数目，结果显示，转染BCL11A抑制剂的施万细胞中Ki67阳性细胞低于抑制剂对照组，表明BCL11A抑制剂能降低施万细胞的增殖。
实施例6细胞划痕愈合实验
取实施例2获得的施万细胞接种于PLL包被的且内置有划痕模具的6孔板，移除划痕模具时拍摄记录空白面积，记为0小时。继续培养9小时后再次拍摄记录空白面积，使用Image Pro Plus(Media Cybernetics,Rockville,MD,USA)计算相对空白区域，检测施万细胞的迁移能力。
图3A为高倍显微镜下细胞划痕愈合实验图(比例尺为100μm)。图3B为转染PF4抑制剂施万细胞的迁移速率，结果显示，转染BCL11A抑制剂的施万细胞中空白面积更多，表明转染BCL11A抑制剂的施万细胞迁移速率低于抑制剂对照组，说明BCL11A抑制剂能降低施万细胞的迁移速率。
实施例7Transwell迁移实验
取实施例2获得的施万细胞，用DMEM培养基制备成细胞悬液，接种于fibronectin包被的8μm孔径的Transwell小室上室，将完全培养基加入Transwell下室，培养24小时后，使用结晶紫进行染色，用棉签擦除Transwell上表面残留细胞，对迁移至下表面的细胞进行拍照观察，使用33％的冰醋酸洗脱结晶紫，酶标仪测定570nm处的OD值，检测施万细胞的迁移能力。
图3C为高倍显微镜下Transwell迁移实验图(比例尺为50μm)。图3D为转染BCL11A抑制剂施万细胞的迁移速率，结果显示，转染BCL11A抑制剂的施万细胞中迁移至Transwell下表面的细胞量更少，表明转染BCL11A抑制剂的施万细胞迁移能力低于抑制剂对照组，说明BCL11A抑制剂能降低施万细胞的迁移能力。
实施例8活细胞工作站实验
取实施例2获得的施万细胞接种于活细胞培养皿，37℃培养箱中静置30min，待细胞贴壁后，置于活细胞工作站，于活细胞工作站每隔5分钟拍摄一次，共拍摄12小时，使用ImageJ(National Institutes of Health Bethesda,MD,USA)分析施万细胞的运动距离，绘制施万细胞的运动轨迹和速率分布图。
图3E和图3F分别为转染BCL11A抑制剂施万细胞的运动轨迹和运动速率，结果显示，转染BCL11A抑制剂的施万细胞中运动距离和运动速率均小于抑制剂对照组，说明BCL11A抑制剂能降低施万细胞的运动和迁移。
实施例9大鼠坐骨神经夹伤和体内EdU实验
取成年雄性SD大鼠(180-220g)，腹腔注射复合麻醉剂，使用眼科剪在左侧股骨进行1cm的切口，暴露皮下肌肉后，眼科剪顺着肌肉纹理进行钝性分离，显微镊分离坐骨神经，使用无齿止血钳夹伤坐骨神经30秒，构建大鼠左后肢坐骨神经3mm夹伤模型。使用微量注射器将BCL11A抑制剂(si-Bcl11a)和抑制剂对照(si-Ctr)组注入压伤部位的神经外膜。神经损伤时和损伤后3天，大鼠腹腔注射EdU溶液，EdU注射1天后(即神经损伤1天和4天后)，收集大鼠坐骨神经段，进行厚度为12μm的冰冻切片，组织免疫荧光染色观察施万细胞在大鼠体内的增殖和迁移情况以及轴突再生情况。
图4A和图4B为高倍显微镜下组织免疫组化图(比例尺为1000μm)。图4A为抑制BCL11A对大鼠坐骨神经夹伤后施万细胞增殖和迁移的影响，图4C为神经损伤1天和4天后，施万细胞相对增殖率，结果显示，注射BCL11A抑制剂的大鼠体内施万细胞增殖率低于注射抑制剂对照组，说明BCL11A抑制剂能降低大鼠体内施万细胞的增殖。图4B为抑制BCL11A对大鼠坐骨神经夹伤后轴突再生的影响，图4D为神经损伤1天和4天后，再生轴突相对再生长度，结果显示，注射BCL11A抑制剂的大鼠体内轴突再生长度低于注射抑制剂对照组，说明BCL11A抑制剂能降低大鼠体内受损轴突的再生。
序列表
<110> 南通大学
<120> 转录因子BCL11A在制备施万细胞调控药物中的应用
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Claims (8)
1.转录因子BCL11A在制备施万细胞调控药物中的应用。
2.如权利要求1所述的应用，其特征在于所述转录因子BCL11A为人或鼠源转录因子BCL11A。
3.如权利要求1所述的应用，其特征在于所述转录因子BCL11A具有与SEQ ID NO:1所示序列95％及以上同源的氨基酸序列。
4.如权利要求1所述的应用，其特征在于BCL11A作为药物设计靶点设计抑制BCL11A表达的药物，抑制施万细胞的增殖和迁移。
5.如权利要求4所述的应用，其特征在于所述抑制BCL11A表达的药物是BCL11A的蛋白类抑制剂、核酸适配体和/或BCL11A编码基因的干扰RNA、gRNA、microRNA、小分子化合物抑制剂中的一种或几种。
6.如权利要求4所述的应用，其特征在于所述抑制BCL11A表达的药物为Bcl11a基因的小干扰RNA。
7.如权利要求6所述的应用，其特征在于所述Bcl11a基因的小干扰RNA，其靶序列如SEQID NO:3所示。
8.如权利要求1所述的应用，其特征在于施万细胞调控药物包括神经损伤后施万细胞大量增殖引发施万细胞的分化障碍或施万细胞过度生长疾病如神经鞘瘤。
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