Cell Stem Cell:骨骼肌干细胞如何应对环境污染物刺激?

2019-04-19 阿童木 BioArt

骨骼肌卫星细胞(Muscle satellite cells, MuSCs)是位于肌纤维质膜和基板之间的成体肌源性干细胞,正常生理条件下处于G0期静止状态,转录因子PAX7在MuSCs维持过程中发挥了重要作用。在外伤或病理状态下,PAX7+ MuSCs会从G0期激活进入G1期,表达肌肉生长因子MYOD,PAX7表达下调,诱导分化为肌原细胞,使肌肉组织得以修复。

骨骼肌卫星细胞(Muscle satellite cells, MuSCs)是位于肌纤维质膜和基板之间的成体肌源性干细胞,正常生理条件下处于G0期静止状态,转录因子PAX7在MuSCs维持过程中发挥了重要作用。在外伤或病理状态下,PAX7+ MuSCs会从G0期激活进入G1期,表达肌肉生长因子MYOD,PAX7表达下调,诱导分化为肌原细胞,使肌肉组织得以修复。

世界卫生组织公布的数据显示,每年因空气污染造成的死亡人数达到700万人。近年来的研究表明,环境污染物能通过影响干细胞的稳态调节从而发挥有害作用,导致干细胞分化潜能和自我更新能力的改变。

2019年4月18日,法国Mondor生物医学研究所(IMRB)的Frédéric Relaix领导的团队在Cell Stem Cell上发表长文PAX3 Confers Functional Heterogeneity in Skeletal Muscle Stem Cell Responses to Environmental Stress,揭示了MuSCs受到环境污染物胁迫后,通过PAX3诱导mTORC1表达,进行功能异质性调控,以保护骨骼肌免受毒害。

正常小鼠注射环境中广泛存在的高毒性污染物——2,3,7,8-四氯二苯并二恶英(TCDD)后,骨骼肌稳态发生变化,PAX7+ MuSCs数量减少并分化为肌纤维细胞。PAX7同源转录因子PAX3在一部分肌肉特异性干细胞亚群中表达,TCDD胁迫后发生分化且数量减少的PAX7+ MuSCs主要是PAX3- MuSCs,而PAX3+ MuSCs的数量未发生明显变化。

有研究表明TCDD等污染物对细胞的毒害是通过芳香烃受体(aryl hydrocarbon receptor, AHR)通路介导的。随后作者构建了MuSCs特异性AHR条件敲除小鼠模型(AHR cKO),发现TCDD胁迫会导致正常小鼠AHR通路下游基因和Pax3表达上调,一些MuSCs亚群发生异常激活,而AHR敲除小鼠受TCDD胁迫后上述基因表达水平未发生显着变化,且MuSCs的异常激活受阻。AHR敲除实验证明Pax3位于AHR通路下游,且AHR通路在TCDD诱导的PAX3- MuSCs异常激活中发挥了重要作用。

作者进一步构建了PAX3 cKO小鼠,证明PAX3在TCDD胁迫后的PAX3+ MuSCs中发挥了保护作用,且PAX3的表达与AHR通路的激活存在相关性。通过分析mTORC信号标志物S6核糖体蛋白磷酸化(p-S6)水平,作者发现TCDD胁迫会导致mTORC1通路发生PAX3依赖性激活,而mTORC1抑制剂处理会导致PAX3+ MuSCs对TCDD的刺激更加敏感,而且表现出与PAX3- MuSCs类似的MYOD激活水平。因此,PAX3对MuSCs适应性反应的调控是通过调节mTORC1信号通路实现的。

综上所述,在受到污染物TCDD胁迫后,PAX3- MuSCs存活率下降,异常激活,并发生零星的肌纤维融合,而PAX3+ MuSC则能通过mTORC1依赖性的警报反应来保护自身不受污染物的毒害,证明PAX3能通过调节MuSCs的功能异质性来抵抗环境污染物的刺激。环境污染已成为当今社会所面临的公共问题,严重威胁着人类健康,本文为探明干细胞对抗环境污染胁迫的分子机制提供了实验依据。

原始出处:
AudreyDer Vartanian,MarieQuétin,StéphanieMichineau,et al.PAX3 Confers Functional Heterogeneity in Skeletal Muscle Stem Cell Responses to Environmental Stress,Cell Stem Cell,18 April 2019,https://doi.org/10.1016/j.stem.2019.03.019

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    2019-07-11 维他命
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  4. [GetPortalCommentsPageByObjectIdResponse(id=1794686, encodeId=84071e9468674, content=<a href='/topic/show?id=82b416e79f5' target=_blank style='color:#2F92EE;'>#stem cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16779, encryptionId=82b416e79f5, topicName=stem cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=4c37265, createdName=hb2008ye, createdTime=Thu Sep 12 08:22:00 CST 2019, time=2019-09-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1961507, encodeId=ade3196150e33, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=c3ff68, createdName=维他命, createdTime=Thu Jul 11 07:22:00 CST 2019, time=2019-07-11, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2049653, encodeId=b60a204965360, content=<a href='/topic/show?id=e8f968458f7' target=_blank style='color:#2F92EE;'>#环境污染物#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=68458, encryptionId=e8f968458f7, topicName=环境污染物)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=39a0295, createdName=kksonne, createdTime=Sun Mar 29 18:22:00 CST 2020, time=2020-03-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1871227, encodeId=311718e122790, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Fri Nov 08 23:22:00 CST 2019, time=2019-11-08, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2010826, encodeId=fa16201082621, content=<a href='/topic/show?id=5311101929de' target=_blank style='color:#2F92EE;'>#骨骼肌干细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101929, encryptionId=5311101929de, topicName=骨骼肌干细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=30bd35, createdName=一叶知秋, createdTime=Sat Jan 25 23:22:00 CST 2020, time=2020-01-25, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1333088, encodeId=99f31333088da, content=<a href='/topic/show?id=4339101926f4' target=_blank style='color:#2F92EE;'>#骨骼肌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=101926, encryptionId=4339101926f4, topicName=骨骼肌)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTIuNQXObUwZmFG3VcZa2uhFq27sY7vfTowUhQCgRj2bj1odUibMF4sFXpuRLf6IE5t5yGVDSiaOoOcQ/132, createdBy=1e622500088, createdName=ms1065684921169360, createdTime=Sun Apr 21 06:22:00 CST 2019, time=2019-04-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1472641, encodeId=d58a14e2641b8, content=<a href='/topic/show?id=ba4a6436107' target=_blank style='color:#2F92EE;'>#污染#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=64361, encryptionId=ba4a6436107, topicName=污染)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=dfe67217539, createdName=小刀医生, createdTime=Sun Apr 21 06:22:00 CST 2019, time=2019-04-21, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1482241, encodeId=8220148224139, content=<a href='/topic/show?id=8cc416e78f3' target=_blank style='color:#2F92EE;'>#STEM#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16778, encryptionId=8cc416e78f3, topicName=STEM)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d1067833268, createdName=12498bb3m92(暂无昵称), createdTime=Sun Apr 21 06:22:00 CST 2019, time=2019-04-21, status=1, ipAttribution=)]
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骨骼肌在受伤后失去愈合的能力是变老的一大表现,匹兹堡大学(UPMC)近日的新研究表明,“炙手可热”的“长寿蛋白”Klotho既是罪魁祸首,也是恢复老年骨骼肌再生缺陷的一个潜在靶标。