CN114207112A - 毛乳头细胞的培养方法 - Google Patents
毛乳头细胞的培养方法 Download PDFInfo
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Abstract
本发明提供维持毛囊诱导能力并且高效地培养毛乳头细胞的方法。毛乳头细胞的培养方法中,在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞。
Description
技术领域
本发明涉及毛乳头细胞的培养方法。
背景技术
毛乳头细胞(dermal papilla)是处于毛囊基部的来自间充质细胞的细胞,发挥通过向毛囊上皮干细胞发送分化信号,而分化诱导为毛囊的作用。
即,毛乳头细胞在毛囊再生中与毛囊上皮干细胞一起是不可或缺的细胞,只要能够从少数毛囊采集毛乳头细胞并大量培养,则能够有助于毛发再生治疗及毛发的再生研究。
但是,毛乳头细胞具有的毛囊诱导能力会随着培养传代次数增加而消失。因此,一直以来需要在维持毛囊诱导能力的状态下培养毛乳头细胞的技术,例如,报告了在BMP-2/BMP-4系材料和WNT系材料的存在下培养毛乳头细胞(专利文献1)、在饲养细胞上进行培养(专利文献2)、培养成球状(非专利文献1)等。
现有技术文献
专利文献
专利文献1:国际公开第2010/021245号
专利文献2:日本专利第5164439号公报
非专利文献
非专利文献1:ACS Appl Master Interfaces,2016,8:5906-5916
发明内容
本发明涉及以下的发明。
1)一种毛乳头细胞的培养方法,其在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞。
2)一种毛乳头细胞的毛囊诱导能力的维持或促进方法,其包括在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞的步骤。
3)一种毛乳头细胞的毛囊诱导能力维持或促进剂,其以选自界面蛋白及其片段中的至少1种为有效成分。
4)选自界面蛋白及其片段中的至少1种在制造毛乳头细胞的毛囊诱导能力维持或促进剂中的应用。
5)选自界面蛋白及其片段中的至少1种在维持或促进毛乳头细胞的毛囊诱导能力中的应用。
6)选自界面蛋白及其片段中的至少1种,其用于维持或促进毛乳头细胞的毛囊诱导能力。
附图说明
图1是对培养毛乳头细胞进行了碱性磷酸酶活性染色的显微镜照片。
图2是表示培养毛乳头细胞的各种基因表达的变化的图表。
图3是表示来自培养多能干细胞的毛乳头细胞的增殖的显微镜照片。
图4是表示来自培养多能干细胞的毛乳头细胞的各种基因表达的变化的图表。
具体实施方式
本发明的课题在于,提供维持毛囊诱导能力并且高效地培养毛乳头细胞的方法。
本发明的发明人对毛乳头细胞的培养条件进行了各种研究,结果发现,通过在界面蛋白或其片段存在的条件下培养毛乳头细胞,能够在维持毛囊诱导能力的同时进行增殖。
根据本发明,毛乳头细胞能够不降低毛囊诱导能力地容易地增殖。由此,使用具有毛囊诱导能力的培养毛乳头细胞的体外(in vitro)实验变得容易,另外,对从患者自身的毛发采集的毛乳头细胞进行分离、培养,再次返回至患者自身那样的毛发的再生变得容易。
在本发明中,“毛乳头细胞”是位于毛囊最底部的间充质细胞,担负为了毛囊的自我再生而向毛囊上皮干细胞发送活化信号的作用。此外,毛乳头细胞局部存在于毛乳头,与局部存在于骨髓、脂肪、关节滑膜、牙髓等的间叶系干细胞有明确区别。
本发明中使用的毛乳头细胞能够使用来自人、小鼠、大鼠、兔、豚鼠、山羊、猪、牛等哺乳动物的皮肤的毛乳头细胞,优选为来自人皮肤的毛乳头细胞。就皮肤而言,只要毛乳头保持正常的生理功能,就能够选择不限于头发而属于体毛等的皮肤,但优选为头皮。人头皮能够使用通过例如外科手术等采集的头皮,从在显微镜下分离的生长期毛囊采集毛乳头细胞。
供于培养的毛乳头细胞能够采用公知的方法(例如,Tissue Eng.2007,13:975-82.)从采集的皮肤进行制备。即,在实体显微镜下从采集的头皮组织分离生长期毛囊,然后将分离的毛乳头细胞静置于培养用培养皿上,在包含10%牛血清和FGF-2的DMEM培养基中,在CO2恒温箱内在37℃、5%CO2、湿度100%条件下培养数天,由此,能够分离毛乳头细胞。
另外,本发明中使用的毛乳头细胞也可以是从胚胎干细胞(ES细胞)、胚胎癌细胞(EC细胞)、胚胎生殖干细胞(EG细胞)、iPS细胞等多能干细胞分化诱导而制作的来自多能干细胞的毛乳头细胞。作为多能干细胞,优选为来自人的多能干细胞,更优选为人iPS细胞。作为来自多能干细胞的毛乳头细胞,能够使用通过公知的方法(例如,日本专利第6304818号公报)对多能干细胞进行分化诱导而制作的来自皮肤的多能前体细胞(SKPs)等作为毛乳头细胞。
在本发明中,毛乳头细胞的培养在选自界面蛋白及其片段中的至少1种的存在下进行。
“界面蛋白(Emilin)”是指构成细胞外基质的、作为分子量115kDa的糖蛋白的弹性蛋白微原纤维界面因子(elastin microfibril interface-located protein)。目前为止,发现有界面蛋白-1、界面蛋白-2、界面蛋白-3,形成界面蛋白质家族。
其中,关于界面蛋白-1,其功能明确,报告了在皮肤中存在于弹性蛋白和微细纤维的界面,通过调节弹性蛋白沉积,而与皮肤的弹性有关(日本牙周病学会会志2004 46:175-184)。
界面蛋白在C末端侧存在作为整联蛋白结合部位的gC1q结构域,在N末端侧存在富含半胱氨酸的EMI结构域,参与多聚体形成。界面蛋白形成同型三聚物,发挥作用。
作为本发明的界面蛋白,其来源没有特别限定,能够使用来自各种生物、优选来自哺乳动物的界面蛋白。作为哺乳动物,例如可以列举人、小鼠、大鼠、牛、猪等,但没有限定。其中,特别优选使用来自人的界面蛋白。另外,也可以是重组体。
人界面蛋白的基因及氨基酸序列的信息能够从公知的数据库(GenBank等)获取,人界面蛋白-1作为NP_008977.1、人界面蛋白-2作为NP_114437.2、人界面蛋白-3作为NP_443078.1进行登录。其中,优选为人界面蛋白-1,将其氨基酸序列由序列编号1表示。
作为界面蛋白片段,可以举出界面蛋白的部分肽,例如能够例示C末端片段等。优选为界面蛋白-1的部分肽。gC1q结构域是位于从界面蛋白的C末端侧起120~160个氨基酸区域的整联蛋白结合部位(J Biol Chem.2003,278:6160-6167.)。因此,可以说本发明的界面蛋白片段是适当具有整联蛋白结合活性的界面蛋白的部分肽。界面蛋白片段具有整联蛋白结合活性能够通过ELISA法等确认。
在本发明中,作为适合的界面蛋白片段,具体而言,可以列举:界面蛋白-1的C末端片段、包含gC1q结构域的界面蛋白-1的片段、更优选为由120~200个氨基酸构成的界面蛋白-1的C末端片段,详细而言,可以举出包含gC1q结构域的界面蛋白-1的C末端片段,更详细而言,可以举出包含由120~160个氨基酸构成的gC1q结构域的界面蛋白-1的C末端片段。
本发明的界面蛋白或界面蛋白片段也可以由在该蛋白质或肽中缺失、取代或添加1个或多个氨基酸的氨基酸序列构成,且为具有整联蛋白结合活性的蛋白质或肽。作为该蛋白质或肽,例如可以举出由该蛋白质或肽中的gC1q结构域以外的部分的缺失、取代或添加1个或多个氨基酸的氨基酸序列构成的蛋白质或肽。
在此,多个例如可以为2~10个,也可以为2~8个,也可以为2~6个,也可以为2~4个。
界面蛋白能够通过从例如界面蛋白高表达细胞纯化的方法或作为重组蛋白制造。界面蛋白片段的制造方法也没有特别限定,例如,可以列举通过蛋白质分解酶消化全长界面蛋白,对目标片段进行分离、纯化的方法、以及作为重组蛋白而制造的方法等。重组界面蛋白、重组界面蛋白片段能够通过适当采用公知的基因重组技术而制造。即,能够通过如下操作来制造,分别获取编码全长蛋白或部分蛋白的DNA,将该DNA分别插入表达载体,将该表达载体导入适当的宿主细胞进行表达,通过公知的方法纯化形成了三聚物的蛋白质。
另外,上述的界面蛋白或其片段也可以包含它们的构建、分离或纯化中使用的序列、例如标签序列、接头序列等。即,作为一个方式,在本发明的界面蛋白或其片段中包括向界面蛋白或界面蛋白片段的末端添加了标签序列等氨基酸的方式、例如向N末端添加了6×His标签序列的方式等。
本发明的毛乳头细胞的培养条件只要能够增殖毛乳头细胞即可,除了在选自界面蛋白及其片段中的至少1种的存在下进行以外,没有特别限制。例如,可以在包含选自界面蛋白及其片段中的至少1种的培养基材上培养毛乳头细胞,另外,也可以将选自界面蛋白及其片段中的至少1种添加到培养基中来培养毛乳头细胞。
作为包含选自界面蛋白及其片段中的至少1种的培养基材的例子,可以举出具有含有该选自界面蛋白及其片段中的至少1种的涂布剂的培养基材(例如板、网、培养皿等),作为其例子,可以举出利用包含选自界面蛋白及其片段中的至少1种的涂布剂进行涂布,由此,吸附有选自界面蛋白及其片段中的至少1种的培养基材。
另外,在向培养基中添加选自界面蛋白及其片段中的至少1种的情况下,可以在毛乳头细胞的接种之前,向培养基添加选自界面蛋白及其片段中的至少1种,或者也可以与毛乳头细胞一起向培养基中添加选自界面蛋白及其片段中的至少1种。
此外,也可以在包含选自界面蛋白及其片段中的至少1种的培养基材或涂布剂、培养基中包含界面蛋白或其片段以外的支架材料或细胞粘附分子。作为界面蛋白或其片段以外的支架材料或细胞粘附分子,例如,能够列举胶原蛋白、弹性蛋白、层粘连蛋白、蛋白多糖、葡萄糖胺聚糖等细胞外基质构成成分,其中,优选选择相当于毛根部的细胞外基质构成成分的、层粘连蛋白、I型胶原蛋白或IV型胶原蛋白。
就包含选自界面蛋白及其片段中的至少1种的培养基材中的该界面蛋白或其片段的含量而言,该培养基材与培养物接触的面积每1cm2,只要优选为0.05~50μg,更优选为0.1~10μg,更优选为0.2~3μg即可。例如,只要通过每1cm2涂布面积,包含优选0.05~50μg、更优选0.1~10μg、更优选0.2~3μg的界面蛋白或其片段的涂布剂,对该培养基材进行涂布处理,使界面蛋白或其片段吸附于该培养基材即可。
另外,作为每1mL培养基的最终浓度,可以以优选成为0.1~100μg,更优选成为0.2~20μg的方式调整添加了选自界面蛋白及其片段中的至少1种的培养基中的界面蛋白或其片段的含量。
作为培养器,只要能够培养细胞,材质和形状就没有特别限定。例如,材质可以使用塑料或玻璃等,除了培养皿之外,也能够使用具有圆底型或研钵型等形状的底面的孔板。
具体而言,例如,可以列举组织培养培养皿(例如,Corning公司制的细胞培养表面处理后培养皿(产品编号:430165)和IWAKI公司制的组织培养用培养皿(产品编号:3000-035)。
培养液(培养基)能够直接使用动物细胞的培养中使用的市售的营养培养基或添加添加剂进行改良后使用。作为已知的培养基,例如能够列举:MEM培养基(MinimumEssential Medium,最低基本培养基)、BME培养基(Basal Medium Eagle)、IMDM培养基(Iscove’sModified Dulbecco’s Medium)、D-MEM培养基(Dulbecco’s Modified Eagle’sMedium)、Ham培养基(Ham’s F12)、RPMI培养基(Roswell Park Memorial Institutemedium)、Fischer’s培养基、毛乳头细胞增殖培养基及它们的混合培养基等。
作为添加剂,可以是含血清培养基,也可以是无血清培养基,还可以是含有血清替代物的培养基。作为该血清替代物,可以列举:白蛋白、转铁蛋白、脂肪酸、胶原蛋白前体、微量元素(例如锌、硒等)、营养因子(EGF(表皮生长因子)、bFGF(碱性成纤维细胞生长因子)等)、B-27(商标)添加剂、N2添加剂、knockout血清替代物、2-巯基乙醇。另外,根据需要可以列举维生素、缓冲剂、无机盐类、抗生素(例如青霉素、卡那霉素、链霉素)等通常用于培养基的成分。
培养开始时的细胞的接种密度没有特别限定,例如,相对于培养器为0.15×104~10×104cells/cm2,优选为0.5×104~2.0×104cells/cm2。
培养条件没有特别限定,培养温度例如为30~40℃,优选为36℃~38℃,另外,CO2浓度例如为3~10%,优选为4~6%。另外,氧浓度例如为1~25%,优选为2~20%。培养优选进行至细胞的集落的密度相对于培养器到达80%左右。
这样,培养的毛乳头细胞维持毛囊诱导能力。具有毛囊诱导能力的确认能够通过评价报告了其活性与毛囊诱导能力的相关性的碱性磷酸酶(ALP)活性、用于发挥毛囊诱导能力的蛋白质和/或编码该蛋白质的基因的表达的有无、通过显微镜观察的细胞形态等而进行。例如,蛋白质的表达能够通过利用了抗原抗体反应的方法等确认,基因的表达能够通过Northern印迹法、利用了聚合酶链式反应(PCR)等的方法等进行确认。
此外,作为当毛囊诱导能力变高时其表达增加的分子,可以列举:碱性磷酸酶(ALP)、Wingless related MMTV integration site 5A(WNT5A;参与胎儿期的毛囊产生)、Bone morphogenetic protein 4(骨形成发生蛋白4)(BMP4;参与胎儿期的毛囊产生)、Lymphoid enhancer binding factor 1(淋巴样增强结合因子1)(LEF1;参与毛囊胚芽产生时的E-cadherin(E-钙黏着蛋白)的表达抑制)、Low-density lipoprotein receptor-related protein 4(低密度脂蛋白受体相关蛋白4)(LRP4;毛乳头细胞标志物)等,作为当毛囊诱导能力变高时其表达降低的分子,报告了Dickkopf-1(DKK-1;脱发患者中高表达)(文献;J Cell Sci.2012125:4114-4125)。
这样,根据将本发明的毛乳头细胞在选自界面蛋白及其片段中的至少1种的存在下培养的方法,能够维持或促进毛乳头细胞的毛囊诱导能力。因此,界面蛋白或其片段能够成为在毛乳头细胞的培养时向培养基中添加等而被使用的毛囊诱导能力的维持或促进剂。
关于上述的实施方式,在本发明中还公开以下的方式。
<1>一种毛乳头细胞的培养方法,其在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞。
<2>根据<1>的方法,其中,在包含选自界面蛋白及其片段中的至少1种的培养基材上进行,或者通过将选自界面蛋白及其片段中的至少1种添加至培养基中而进行。
<3>根据<2>的方法,其中,在使用界面蛋白或其片段以外的支架材料或细胞粘附分子进行了涂布的培养器中,添加选自界面蛋白及其片段中的至少1种进行培养。
<4>根据<1>~<3>中任一项的方法,其中,作为每1mL培养基的最终浓度,以成为0.1~100μg、优选成为0.2~20μg的方式调整界面蛋白或其片段在培养基中的含量。
<5>根据<2>的方法,其中,就包含选自界面蛋白及其片段中的至少1种的培养基材中的该界面蛋白或其片段的含量而言,该培养基材与培养物接触的面积每1cm2,上述含量为0.05~50μg,优选为0.1~10μg,更优选为0.2~3μg。
<6>根据<1>~<5>中任一项的方法,其中,界面蛋白为界面蛋白-1。
<7>根据<1>~<5>中任一项的方法,其中,界面蛋白的片段包含gC1q结构域。
<8>根据<7>的方法,其中,界面蛋白的片段为界面蛋白-1的C末端片段。
<9>根据<7>的方法,其中,界面蛋白的片段为由120~200个氨基酸构成的界面蛋白-1的C末端片段。
<10>一种毛乳头细胞的毛囊诱导能力的维持或促进方法,其包括在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞的步骤。
<11>一种毛乳头细胞的毛囊诱导能力维持或促进剂,其将选自界面蛋白及其片段中的至少1种作为有效成分。
<12>选自界面蛋白及其片段中的至少1种在制造毛乳头细胞的毛囊诱导能力维持或促进剂中的应用。
<13>选自界面蛋白及其片段中的至少1种在维持或促进毛乳头细胞的毛囊诱导能力中的应用。
<14>用于维持或促进毛乳头细胞的毛囊诱导能力的选自界面蛋白及其片段中的至少1种。
<15>在上述<11>~<14>中,界面蛋白为界面蛋白-1。
<16>在上述<11>~<14>中,界面蛋白的片段包含gC1q结构域。
<17>在上述<16>中,界面蛋白的片段为界面蛋白-1的C末端片段。
<18>在上述<16>中,界面蛋白的片段为由120~200个氨基酸构成的界面蛋白-1的C末端片段。
实施例
参考例1人重组EMILIN-1C末端片段的制作
作为界面蛋白片段,通过以下所示的方法制作人重组EMILIN-1C末端片段(以下,记载为“EM1-C”)。
首先,将通过Super ScriptTM III First-Strand Synthesis System(商品名,Invitrogen公司)对Human Fetal Heart Total RNA(人胎心总RNA)(CLONTECH公司)进行逆转录得到的cDNA作为模板,使用以下的3种引物组进行PCR,对编码人EMILIN-1片段的cDNA进行扩增。
(i)人EMILIN-1第一片段扩增用引物
5’-atatatgctagccactgtggagcgccccgccatg-3’(正向引物,序列编号2)
5’-tccctgccccgcggctcctc-3’(反向引物,序列编号3)
(ii)人EMILIN-1第二片段扩增用引物
5’-atgtcgtggccggctcagtgacagtg-3’(正向引物,序列编号4)
5’-cctcctgctgcagcctgttaatctcagaaatgatacggtc-3’(反向引物,序列编号5)
(iii)人EMILIN-1第三片段扩增用引物
5’-gaccgtatcatttctgagattaacaggctgcagcaggagg-3’(正向引物,序列编号6)
5’-atatataagcttctaatgatgatgatgatgatgcgcgtgttcaagctctgggtcccc-3’(反向引物,序列编号7)
接着,将编码人EMILIN-1第二片段和第三片段的cDNA作为模板,使用以下的引物组进行PCR,将编码第二片段和第三片段连结而成的片段的cDNA进行扩增。
(iv)编码第二片段和第三片段连结而成的片段的cDNA扩增用引物
5’-atgtcgtggccggctcagtgacagtg-3’(正向引物,与序列编号4相同)
5’-atatataagcttctaatgatgatgatgatgatgcgcgtgttcaagctctgggtcccc-3’(反向引物,与序列编号7相同)
编码人EMILIN-1第一片段的cDNA用限制性内切酶NheI和SacII进行酶消化,编码第二片段和第三片段连结而成的片段的cDNA用限制性内切酶SacII和HindIII进行酶消化。
将哺乳细胞用表达载体pSecTag2A(Invitrogen公司)用限制性内切酶NheI和HindIII切断,在该部位插入进行了上述酶消化得到的编码人EMILIN-1片段的各cDNA,制作人全长EMILIN-1的表达载体。
接着,将人全长EMILIN-1的表达载体作为模板,进行使用以下引物的PCR,将编码人EMILIN-1的C末端片段(Ala845-Ala995多肽链[将除去了分泌信号的人EMILIN-1氨基酸序列N末端残基Ala作为第1位])的cDNA进行扩增。
(v)人EMILIN-1的C末端片段扩增用引物
5’-ccaggttccactggtgaccatcatcatcatcatcatgaggagggacaagcacaggccggc-3’(正向引物,序列编号8)
5’-atatataagcttctacgcgtgttcaagctctgggtccccatagag-3’(反向引物,序列编号9)
另外,将哺乳细胞用表达载体pSecTag2A(Invitrogen公司)作为模板,进行使用以下引物的PCR,将pSecTag2A表达载体的编码Igκ分泌信号(Met-Glu-Thr-Asp-Thr-Leu-Leu-Leu-Trp-Val-Leu-Leu-Leu-Trp-Val-Pro-Gly-Ser-Thr-Gly-Asp(序列编号10))和6×His标签的cDNA进行扩增。
(vi)Igκ分泌信号扩增用引物
5’-CGGTAGGCGTGTACGGTGGG-3’(正向引物,序列编号11)
5’-atgatgatgatgatgatggtcaccagtggaacctggaaccc-3’(反向引物,序列编号12)
将上述制作的编码Igκ分泌信号的cDNA和编码人EMILIN-1的C末端片段的cDNA作为模板,进行使用以下引物的PCR,将编码人重组EMILIN-1C末端片段(EM1-C)(在N末端侧包含Igκ分泌信号和6×His标签)的cDNA进行扩增。
(vii)编码EM1-C的cDNA扩增用引物
5’-CGGTAGGCGTGTACGGTGGG-3’(正向引物,与序列编号11相同)
5’-atatataagcttctacgcgtgttcaagctctgggtccccatagag-3’(反向引物,与序列编号9相同)
将扩增的cDNA通过限制性内切酶NheI和HindIII切出,插入哺乳细胞用表达载体pSecTag2A(Invitrogen公司)的对应部位,制作EM1-C的表达载体。
EM1-C的表达通过将制作得到的表达载体导入来自人肾脏的293F细胞(购自Invitrogen公司)而进行。使用转染试剂293fectin(商品名,Invitrogen公司)780μL和Opti-MEM(商品名,Invitrogen公司)42mL向600mL的293F细胞(1.0×106个/mL)转染表达载体600μg,进行48小时培养后,回收培养液。培养液以1000×g离心15分钟,将其上清液进一步以15000×g离心30分钟,除去细胞和不溶物。将培养上清液转移至塑料制三角烧瓶(Corning公司)中,添加1mL的cOmplete His-tag Purification Resin(商品名,Roche公司)、蛋白酶抑制剂Pefabloc(商品名,Roche公司,最终浓度2000倍稀释)、咪唑(最终浓度5mM)、叠氮化钠(最终浓度0.05%),以4℃一边旋转一边孵育过夜,以批式法吸附目标蛋白质。将悬浮液转移至Econo-柱,回收cOmplete His-tag Purification Resin,用5mM咪唑/TBS(-)(不含Ca、Mg的Tris缓冲生理盐水)清洗后,用250mM咪唑/TBS(-)洗脱。将洗脱的组分合并,并转移至离心式超滤过滤器(NMWL:30K,Millipore公司)中,进行离心浓缩。将浓缩的组分转移至透析盒(MWCO:20K,Thermo Fisher Scientific公司),对PBS(-)(不含Ca、Mg的磷酸缓冲生理盐水)进行透析。回收透析得到的纯化蛋白溶液,通过0.22μm盘式过滤器进行过滤除菌,通过BCA法定量。纯化的EM1-C(在N末端侧包含6×His标签)在SDS-PAGE后进行银染色,确认纯度。
实施例1正常人头发毛乳头细胞的培养
1.细胞培养
在I型胶原包被培养皿100mm(IWAKI:4020-010)上接种正常人头发毛乳头细胞(TOYOBO:CA602t05a),使用毛乳头细胞增殖培养基(TOYOBO:TMTPGM-250)进行培养。使用Accutase(Innovative Cell Technologies:AT104)剥离80%~90%汇合的毛乳头细胞,在I型胶原包被培养皿35mm(IWAKI:4000-010)、或者在每1孔添加2mL的100nM的EM1-C并在37℃静置1小时而涂布后的6孔板(Falcon:353046)上分别以成为0.67×104/cm2或1.0×104/cm2的方式接种,使用毛乳头细胞增殖培养基在37℃、5%CO2的恒温箱中培养3天。
2.毛囊诱导能力的确认(碱性磷酸酶染色)
对培养的毛乳头细胞进行碱性磷酸酶染色。碱性磷酸酶染色使用Blue AlkalinePhosphatase Substrate Kit(蓝色碱性磷酸酶底物试剂盒)(Vector laboratories:SK-5300),且根据所附的操作说明书进行。
将对细胞进行了碱性磷酸酶染色的结果在图1中示出。与在涂布有I型胶原蛋白的板上培养的毛乳头细胞相比,在涂布了EM1-C的板上培养的毛乳头细胞通过碱性磷酸酶活性染色被更强地染色。
根据以上的结果,认为界面蛋白-1使毛乳头细胞的毛囊诱导能力上升。
3.毛乳头细胞的基因表达
通过定量PCR法调查培养的毛乳头细胞的基因表达状况。使用RNeasy Mini kit(QIAGEN:74104)从各样品提取RNA。测定各Total RNA(总RNA)的浓度,使用一定量的totalRNA进行逆转录反应。在逆转录反应中使用了High capacity RNA-to-cDNA Kit(AppliedBiosystems:4387406)。通过定量PCR法测定的基因表达使用得到的cDNA样品1μL和TaqmanProbe(Applied Biosystems:4448892),通过Quant Studio Realtime PCR system(Applied Biosystems)进行检测定量。扩增条件如下,在20μL的反应体系以95、15秒的变性反应、60℃、1分钟退火、延伸反应进行。就各基因表达量而言,根据RPLP0的表达量校正通过ΔCt法算出的值,各个基因表达量将在胶原蛋白-1上培养的毛乳头细胞中的表达量设为1.0以相对值表示。
将通过定量PCR法调查的毛乳头细胞的基因表达的结果在图2中示出。在涂布有EM1-C的板上培养的毛乳头细胞与在涂布了I型胶原蛋白的板上培养的毛乳头细胞相比,确认到表明与毛囊诱导能力相关的碱性磷酸酶(ALP)表达的增加。另外,还确认了参与胎儿期的毛囊产生的Wingless related MMTV integration site 5A(WNT5A)、骨形成发生蛋白4(BMP4)、抑制毛囊胚芽产生时的E-钙黏着蛋白的表达的淋巴样增强结合因子1(LEF1)的表达增加。确认到作为毛乳头细胞标志物的低密度脂蛋白受体相关蛋白4(LRP4)的表达的增加,在脱发患者中表达高的Dickkopf-1(DKK-1)被确认到表达的降低。进而,当在EM1-C上培养毛乳头细胞时,确认到界面蛋白-1基因的表达增加。
根据以上的结果,认为界面蛋白-1具有使毛乳头细胞的毛囊诱导能力上升的可能性。
实施例2来自多能干细胞的毛乳头细胞在界面蛋白-1上的培养
<来自多能干细胞的毛乳头细胞的制备>
1.来自皮肤的多能前体细胞(SKPs)的制作
(1)iPS细胞的培养
作为多能干细胞,使用了来自人的iPS细胞(克隆名称:1231A3)。细胞根据获取机构推荐的培养方法进行维持培养。即,使用StemFit(注册商标)(AK02N,味之素株式会社制)作为人iPS细胞用培养基,在37℃、5%CO2的恒温箱中,根据Sci.Rep,4,2014,3594;DOI:10.1038/srep03594所记载的方法,培养细胞。此时,作为支架用的分子,将人基底膜蛋白多糖(Perlecan)的结构域I(Gly25-Pro196)(以下,也称为Pln-D1)片段与人层粘连蛋白α1链E8片段的C末端部融合得到的层粘连蛋白111E8片段(以下,也称为基底膜蛋白多糖修饰LM111E8、P-LM111E8)〔根据PCT/JP2020/029855、日本特愿2020-132547和日本特愿2019-144899所记载的方法制备〕溶解于DPBS中,使用预先以0.5μg/涂布面积cm2的浓度涂布的培养皿进行了培养。
(2)来自人iPS细胞的神经嵴干(NCS)细胞的制备
基于Nature protocols,2010,5:688-701或Cell reports,2013,3:1140-1152所记载的方法,将(1)中培养的iPS细胞分化成NCS细胞。将该iPS细胞通过包含noggin(R&Dsystems公司制,目录编号:6057-NG-100/CF,500ng/mL)和/或SB431542(TOCRIS公司制,目录编号:1614,10μM)的StemFit(注册商标)AK02N(添加剂C(-))培养基培养5天~2周,由此,诱导向NCS细胞的分化。此外,由于从iPS细胞向NCS细胞分化诱导时不进行传代,所以,在iPS细胞培养时涂布的P-LM111E8直接作为支架用分子存在。
(3)从NCS细胞向SKPs的分化诱导
通过包含B-27(商标)添加剂(Life Technologies公司制,目录编号:17504-044,2质量%)、EGF(R&D systems公司制,目录编号:336-EG-200,20ng/mL)、bFGF(Wako公司制,目录编号:064-04541,40ng/mL)、青霉素/链霉素(Life Technologies公司制,目录编号:15140-122,50U,50μg/mL)、和CHIR99021(Cayman公司制,目录编号:13122,3μM)的DMEM/F12培养基(Life Technologies公司制,目录编号:10565-018),将(2)中制备的NCS细胞培养3~5天,诱导从NCS细胞向SKPs的分化。此外,由于从NCS细胞向SKPs的分化诱导时不进行传代,因此,在iPS细胞培养时涂布的P-LM111E8直接作为支架用分子存在。接着,使用培养细胞分离/分散溶液(商品名:Accutase,BD Biosciences公司制,目录编号:561527),在无P-LM111E8支架下对分化成SKPs的细胞进行传代培养,接着,利用包含B-27(商标)添加剂(2质量%)、EGF(20ng/mL)、bFGF(40ng/mL)、青霉素/链霉素(Life Technologies公司制,目录编号:15140-122,50U,50μg/mL)的D-MEM/F12培养基进一步培养。将得到的SKPs作为毛乳头细胞用于以下的实验中。
<来自多能干细胞的毛乳头细胞在界面蛋白-1上的培养>
1.细胞培养
如上述那样,将来自多能干细胞的SKPs作为毛乳头细胞,分别接种在无涂层培养皿(IWAKI:3000-035)或将0.5μg/cm2的EM1-C以37℃静置1小时而涂布的同培养皿上,使用包含B27 supplement(Life Technologies公司制,目录编号:17504-044,2质量%)、EGF(R&DSystems公司制,目录编号:336-EG-200,20ng/mL)、bFGF(Wako公司制,目录编号:064-04541,40ng/mL)、青霉素/链霉素(Life Technologies公司制,目录编号:15140-122,50U,50μg/mL)的D-MEM/F12培养基(Life Technologies公司制,目录编号:10565-018,)在37℃、5%CO2的恒温箱中培养3天。
将表示这样培养而得到的毛乳头细胞的样子的显微镜照片在图3中示出。关于来自多能干细胞的毛乳头细胞也认为通过在界面蛋白-1上培养,而细胞的生长良好。
2.来自多能干细胞的毛乳头细胞的基因表达
通过定量PCR法调查培养的来自多能干细胞的毛乳头细胞的基因表达状况。使用RNeasy Mini kit从各样品提取RNA。测定各总RNA的浓度,使用一定量的总RNA进行逆转录反应。在逆转录反应中使用了High capacity RNA-to-cDNA Kit。通过定量PCR法测定的基因表达使用得到的cDNA样品1μL和Taqman Probe,通过Quant Studio Realtime PCRsystem进行检测定量。扩增条件如下,在20μL的反应体系中以95℃变性反应15秒、60℃退火1分钟、延伸反应进行。就各基因表达量而言,根据RPLP0的表达量校正通过ΔCt法算出的值,各个基因表达量将在I型胶原蛋白上培养的毛乳头细胞中的表达量设为1.0以相对值表示。
将通过定量PCR法调查的来自多能干细胞的毛乳头细胞的基因表达的结果在图4中示出。当在EM1-C上培养使用P-LM111E8片段制作的来自多能干细胞的毛乳头细胞时,确认到表明与毛囊诱导能力相关的ALP表达的增加。另外,还确认到参与胎儿期的毛囊产生的BMP4、LEF1的表达增加,该LEF1抑制毛囊胚芽产生时的E-钙黏着蛋白的表达。另外,还确认到作为毛乳头细胞标志物的LRP4的表达的增加。
根据以上的结果,认为界面蛋白-1具有使来自多能干细胞的毛乳头细胞的毛囊诱导能力上升的可能性。
序列表
<110> 花王株式会社
国立大学法人大阪大学
<120> 毛乳头细胞的培养方法
<130> KS1676
<150> 2019-145099
<151> 2019-08-07
<160> 12
<170> PatentIn version 3.5
<210> 1
<211> 1016
<212> PRT
<213> 智人
<400> 1
Met Ala Pro Arg Thr Leu Trp Ser Cys Tyr Leu Cys Cys Leu Leu Thr
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Ala Ala Ala Gly Ala Ala Ser Tyr Pro Pro Arg Gly Phe Ser Leu Tyr
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Thr Gly Ser Ser Gly Ala Leu Ser Pro Gly Gly Pro Gln Ala Gln Ile
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Ala Pro Arg Pro Ala Ser Arg His Arg Asn Trp Cys Ala Tyr Val Val
50 55 60
Thr Arg Thr Val Ser Cys Val Leu Glu Asp Gly Val Glu Thr Tyr Val
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Lys Tyr Gln Pro Cys Ala Trp Gly Gln Pro Gln Cys Pro Gln Ser Ile
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Met Tyr Arg Arg Phe Leu Arg Pro Arg Tyr Arg Val Ala Tyr Lys Thr
100 105 110
Val Thr Asp Met Glu Trp Arg Cys Cys Gln Gly Tyr Gly Gly Asp Asp
115 120 125
Cys Ala Glu Ser Pro Ala Pro Ala Leu Gly Pro Ala Ser Ser Thr Pro
130 135 140
Arg Pro Leu Ala Arg Pro Ala Arg Pro Asn Leu Ser Gly Ser Ser Ala
145 150 155 160
Gly Ser Pro Leu Ser Gly Leu Gly Gly Glu Gly Pro Gly Glu Ser Glu
165 170 175
Lys Val Gln Gln Leu Glu Glu Gln Val Gln Ser Leu Thr Lys Glu Leu
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Gln Gly Leu Arg Gly Val Leu Gln Gly Leu Ser Gly Arg Leu Ala Glu
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Asp Val Gln Arg Ala Val Glu Thr Ala Phe Asn Gly Arg Gln Gln Pro
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Ala Asp Ala Ala Ala Arg Pro Gly Val His Glu Thr Leu Asn Glu Ile
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Gln His Gln Leu Gln Leu Leu Asp Thr Arg Val Ser Thr His Asp Gln
245 250 255
Glu Leu Gly His Leu Asn Asn His His Gly Gly Ser Ser Ser Ser Gly
260 265 270
Gly Ser Arg Ala Pro Ala Pro Ala Ser Ala Pro Pro Gly Pro Ser Glu
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Glu Leu Leu Arg Gln Leu Glu Gln Arg Leu Gln Glu Ser Cys Ser Val
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Cys Leu Ala Gly Leu Asp Gly Phe Arg Arg Gln Gln Gln Glu Asp Arg
305 310 315 320
Glu Arg Leu Arg Ala Met Glu Lys Leu Leu Ala Ser Val Glu Glu Arg
325 330 335
Gln Arg His Leu Ala Gly Leu Ala Val Gly Arg Arg Pro Pro Gln Glu
340 345 350
Cys Cys Ser Pro Glu Leu Gly Arg Arg Leu Ala Glu Leu Glu Arg Arg
355 360 365
Leu Asp Val Val Ala Gly Ser Val Thr Val Leu Ser Gly Arg Arg Gly
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Thr Glu Leu Gly Gly Ala Ala Gly Gln Gly Gly His Pro Pro Gly Tyr
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Thr Ser Leu Ala Ser Arg Leu Ser Arg Leu Glu Asp Arg Phe Asn Ser
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Thr Leu Gly Pro Ser Glu Glu Gln Glu Glu Ser Trp Pro Gly Ala Pro
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Gly Gly Leu Ser His Trp Leu Pro Ala Ala Arg Gly Arg Leu Glu Gln
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Leu Gly Gly Leu Leu Ala Asn Val Ser Gly Glu Leu Gly Gly Arg Leu
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Asp Leu Leu Glu Glu Gln Val Ala Gly Ala Met Gln Ala Cys Gly Gln
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Leu Cys Ser Gly Ala Pro Gly Glu Gln Asp Ser Gln Val Ser Glu Ile
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Leu Ser Ala Leu Glu Arg Arg Val Leu Asp Ser Glu Gly Gln Leu Arg
500 505 510
Leu Val Gly Ser Gly Leu His Thr Val Glu Ala Ala Gly Glu Ala Arg
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Gln Ala Thr Leu Glu Gly Leu Gln Glu Val Val Gly Arg Leu Gln Asp
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Arg Val Asp Ala Gln Asp Glu Thr Ala Ala Glu Phe Thr Leu Arg Leu
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Asn Leu Thr Ala Ala Arg Leu Gly Gln Leu Glu Gly Leu Leu Gln Ala
565 570 575
His Gly Asp Glu Gly Cys Gly Ala Cys Gly Gly Val Gln Glu Glu Leu
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Gly Arg Leu Arg Asp Gly Val Glu Arg Cys Ser Cys Pro Leu Leu Pro
595 600 605
Pro Arg Gly Pro Gly Ala Gly Pro Gly Val Gly Gly Pro Ser Arg Gly
610 615 620
Pro Leu Asp Gly Phe Ser Val Phe Gly Gly Ser Ser Gly Ser Ala Leu
625 630 635 640
Gln Ala Leu Gln Gly Glu Leu Ser Glu Val Ile Leu Ser Phe Ser Ser
645 650 655
Leu Asn Asp Ser Leu Asn Glu Leu Gln Thr Thr Val Glu Gly Gln Gly
660 665 670
Ala Asp Leu Ala Asp Leu Gly Ala Thr Lys Asp Arg Ile Ile Ser Glu
675 680 685
Ile Asn Arg Leu Gln Gln Glu Ala Thr Glu His Ala Thr Glu Ser Glu
690 695 700
Glu Arg Phe Arg Gly Leu Glu Glu Gly Gln Ala Gln Ala Gly Gln Cys
705 710 715 720
Pro Ser Leu Glu Gly Arg Leu Gly Arg Leu Glu Gly Val Cys Glu Arg
725 730 735
Leu Asp Thr Val Ala Gly Gly Leu Gln Gly Leu Arg Glu Gly Leu Ser
740 745 750
Arg His Val Ala Gly Leu Trp Ala Gly Leu Arg Glu Thr Asn Thr Thr
755 760 765
Ser Gln Met Gln Ala Ala Leu Leu Glu Lys Leu Val Gly Gly Gln Ala
770 775 780
Gly Leu Gly Arg Arg Leu Gly Ala Leu Asn Ser Ser Leu Gln Leu Leu
785 790 795 800
Glu Asp Arg Leu His Gln Leu Ser Leu Lys Asp Leu Thr Gly Pro Ala
805 810 815
Gly Glu Ala Gly Pro Pro Gly Pro Pro Gly Leu Gln Gly Pro Pro Gly
820 825 830
Pro Ala Gly Pro Pro Gly Ser Pro Gly Lys Asp Gly Gln Glu Gly Pro
835 840 845
Ile Gly Pro Pro Gly Pro Gln Gly Glu Gln Gly Val Glu Gly Ala Pro
850 855 860
Ala Ala Pro Val Pro Gln Val Ala Phe Ser Ala Ala Leu Ser Leu Pro
865 870 875 880
Arg Ser Glu Pro Gly Thr Val Pro Phe Asp Arg Val Leu Leu Asn Asp
885 890 895
Gly Gly Tyr Tyr Asp Pro Glu Thr Gly Val Phe Thr Ala Pro Leu Ala
900 905 910
Gly Arg Tyr Leu Leu Ser Ala Val Leu Thr Gly His Arg His Glu Lys
915 920 925
Val Glu Ala Val Leu Ser Arg Ser Asn Gln Gly Val Ala Arg Val Asp
930 935 940
Ser Gly Gly Tyr Glu Pro Glu Gly Leu Glu Asn Lys Pro Val Ala Glu
945 950 955 960
Ser Gln Pro Ser Pro Gly Thr Leu Gly Val Phe Ser Leu Ile Leu Pro
965 970 975
Leu Gln Ala Gly Asp Thr Val Cys Val Asp Leu Val Met Gly Gln Leu
980 985 990
Ala His Ser Glu Glu Pro Leu Thr Ile Phe Ser Gly Ala Leu Leu Tyr
995 1000 1005
Gly Asp Pro Glu Leu Glu His Ala
1010 1015
<210> 2
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 2
atatatgcta gccactgtgg agcgccccgc catg 34
<210> 3
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 3
tccctgcccc gcggctcctc 20
<210> 4
<211> 26
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 4
atgtcgtggc cggctcagtg acagtg 26
<210> 5
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 5
cctcctgctg cagcctgtta atctcagaaa tgatacggtc 40
<210> 6
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 6
gaccgtatca tttctgagat taacaggctg cagcaggagg 40
<210> 7
<211> 57
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 7
atatataagc ttctaatgat gatgatgatg atgcgcgtgt tcaagctctg ggtcccc 57
<210> 8
<211> 60
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 8
ccaggttcca ctggtgacca tcatcatcat catcatgagg agggacaagc acaggccggc 60
<210> 9
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 9
atatataagc ttctacgcgt gttcaagctc tgggtcccca tagag 45
<210> 10
<211> 21
<212> PRT
<213> 小家鼠
<400> 10
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp
20
<210> 11
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 11
cggtaggcgt gtacggtggg 20
<210> 12
<211> 41
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 12
atgatgatga tgatgatggt caccagtgga acctggaacc c 41
Claims (16)
1.一种毛乳头细胞的培养方法,其特征在于:
在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞。
2.根据权利要求1所述的方法,其特征在于:
培养在包含选自界面蛋白及其片段中的至少1种的培养基材上进行、或者通过将选自界面蛋白及其片段中的至少1种添加至培养基而进行。
3.根据权利要求1或2所述的方法,其特征在于:
界面蛋白为界面蛋白-1。
4.根据权利要求1~3中任一项所述的方法,其特征在于:
界面蛋白的片段包含gC1q结构域。
5.根据权利要求4所述的方法,其特征在于:
界面蛋白的片段为界面蛋白-1的C末端片段。
6.一种毛乳头细胞的毛囊诱导能力的维持或促进方法,其特征在于:
包括在选自界面蛋白及其片段中的至少1种的存在下培养毛乳头细胞的步骤。
7.一种毛乳头细胞的毛囊诱导能力维持或促进剂,其特征在于:
以选自界面蛋白及其片段中的至少1种为有效成分。
8.选自界面蛋白及其片段中的至少1种在制造毛乳头细胞的毛囊诱导能力维持或促进剂中的应用。
9.选自界面蛋白及其片段中的至少1种在维持或促进毛乳头细胞的毛囊诱导能力中的应用。
10.根据权利要求8或9所述的应用,其特征在于:
界面蛋白为界面蛋白-1。
11.根据权利要求8~10中任一项所述的应用,其特征在于:
界面蛋白的片段包含gC1q结构域。
12.根据权利要求11所述的应用,其特征在于:
界面蛋白的片段为界面蛋白-1的C末端片段。
13.用于维持或促进毛乳头细胞的毛囊诱导能力的选自界面蛋白及其片段中的至少1种。
14.根据权利要求13所述的选自界面蛋白及其片段中的至少1种,其特征在于:
界面蛋白为界面蛋白-1。
15.根据权利要求13或14所述的选自界面蛋白及其片段中的至少1种,其特征在于:
界面蛋白的片段包含gC1q结构域。
16.根据权利要求15所述的选自界面蛋白及其片段中的至少1种,其特征在于:
界面蛋白的片段为界面蛋白-1的C末端片段。
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JPS57144247A (en) | 1981-03-02 | 1982-09-06 | Lion Corp | Preparation of n-substituted amino-alcohol compound |
JP3573488B2 (ja) * | 1994-04-11 | 2004-10-06 | 独立行政法人 科学技術振興機構 | 毛乳頭細胞の長期継代培養法 |
JP5164439B2 (ja) | 2007-06-12 | 2013-03-21 | 株式会社 資生堂 | 毛乳頭細胞培養方法 |
JPWO2010021245A1 (ja) | 2008-08-22 | 2012-01-26 | 学校法人慶應義塾 | 毛乳頭細胞の培養方法 |
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JP2020132547A (ja) | 2019-02-15 | 2020-08-31 | 国立大学法人 東京医科歯科大学 | 白髪抑制・改善剤、及び、その製造方法 |
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Non-Patent Citations (1)
Title |
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PAOLA SPESSOTTO等: "β1 Integrin-dependent Cell Adhesion to EMILIN-1 Is Mediated by the gC1q Domain", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 278, no. 8, 21 February 2003 (2003-02-21), pages 6160 - 6167, XP002607693, DOI: 10.1074/JBC.M208322200 * |
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