Developmental Cell:中南大学李吉团队等发现治疗雄性激素性脱发新方法,可激活毛囊再生

2022-07-07 nagashi 生物世界

脱发的原因众多,其中最主要的是雄激素源性脱发(雄脱),占比超过90%,据统计,我国雄激素源性脱发的患病率男性为21.3%,女性为6.0%,且有逐年升高、低龄化发展的趋势。

YingziLiu目前全世界有数以亿计的男性,女性甚至是儿童饱受脱发困扰,遗传、衰老、分娩、癌症治疗、烧伤以及压力等都可能导致脱发。脱发虽然不会造成严重的健康问题,但是因为影响美观,会导致个人形象问题,并因此带来情绪创伤甚至抑郁。

脱发的原因众多,其中最主要的是雄激素源性脱发(雄脱),占比超过90%,据统计,我国雄激素源性脱发的患病率男性为21.3%,女性为6.0%,且有逐年升高、低龄化发展的趋势。

尽管受脱发困扰的群体如此之大,但治疗脱发的方法却十分有限。药物治疗(米诺地尔、非那雄胺)、手术治疗(植发)、物理疗法(中医针灸、低频激光疗法)等方法,并不能长期阻止脱发,更不能实现毛囊再生。近日,FDA 批准了礼来/Incyte开发的口服脱发药物巴瑞替尼(baricitinib),效果显着,但该药物针对的是斑秃,斑秃在脱发中的占比不到2%。

2022年6月30日,中南大学湘雅医院李吉教授团队和加州大学欧文分校 Maksim Plikus 教授团队合作,在 Cell 子刊 Developmental Cell 上发表了题为:Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state 的研究论文。

该研究发现了一种与毛发生长相关的 Hedgehog 信号通路的下游分泌因子——SCUBE3。在正常小鼠皮肤中,SCUBE3 只在生长的真皮乳头(dermal papilla)中表达,而在休止期的毛囊中不表达,微量注射 SCUBE3 蛋白足以激活新的毛发生长,这为雄性激素源性脱发找到一个潜在解决方法。

毛囊是毛发的基本单位,而毛发是由毛囊干细胞(HFSC)生长分化而来。不过,负责生发的毛囊干细胞通常处在休眠状态,只会在新一轮生发周期中迅速活化分裂。此前的研究表明,过度激活毛囊中的Hedgehog信号通路将显着加速小鼠的毛发生长和诱导毛囊增殖。

毛囊干细胞受真皮乳头成纤维细胞的调节,最近的单细胞 RNA 测序(scRNA-seq)研究显示,与毛囊休止期相比,真皮乳头成纤维细胞在毛囊生长期的转录组存在较大差异,并上调多种信号分子,从而促进毛发再生。

在这项最新研究中,为了确定靶向真皮乳头成纤维细胞的基因工具,研究团队筛查了小鼠毛囊细胞的单细胞转录组数据集,并确定 Lepr 是真皮乳头的标记基因。基于此,研究小组构建了 LeprB-Cre 转基因小鼠模型,用以研究毛发生长和毛囊新生的具体过程。

Lepr是毛囊间充质的标记基因

研究人员首先验证在 LeprB-Cre 小鼠的真皮细胞中激活 Hedgehog 信号通路是否会影响毛发的生长。值得注意的是,在正常情况下,Hedgehog 信号通路是胚胎毛发发育和适应性毛发生长激活所必需的。研究结果显示,激活真皮细胞的 Hedgehog 信号通路会刺激小鼠毛发的超活化再生。

激活真皮细胞的Hedgehog信号通路可以刺激小鼠毛发的超活化再生

进一步的单细胞 RNA 测序显示,真皮乳头成纤维细胞中 Hedgehog 信号通路的异位激活使其转录组特征发生变化,激活 Gli1、Alx3、Ebf1、Hoxc8、Sox18 和 Zfp239 的调控网络,这些网络共同上调多种毛发形态发生和毛发生长相关通路的分泌因子,其中就包括非常规 TGF-β 配体——SCUBE3。

Hedgehog信号通路的激活导致转录组特征发生明显变化

SCUBE3 是一种多功能蛋白,它可以以膜蛋白形式增强细胞上的 BMP 和 FGF8 信号,或以其蛋白水解裂解分泌形式增强细胞上的 TGF-β 信号。研究团队发现,在正常小鼠皮肤中,SCUBE3只在生长的真皮乳头中表达,而在休止期的毛囊中不表达。

更重要的是,进一步的研究表明,SCUBE3 是一种毛发生长激活剂,只需微量注射 SCUBE3 蛋白就足以激活毛发生长。此外,SCUBE3 的表达上调伴随着 TGF-β 特异性磷酸化 SMAD2 在上皮发前体细胞中的提前激活,因此药理性 TGF-β 抑制足以逆转 SCUBE3 介导的毛发生长。

微量注射SCUBE3蛋白就足以诱导毛发生长

总而言之,这项研究发现,Hedgehog 信号通路在真皮乳头成纤维细胞的活化和毛发生长中发挥重要作用,而该通路下游的 SCUBE3 信号分子可以刺激毛发的生长,在未来或许将成为治疗雄性激素源性脱发的良药。

据悉,研究团队已经提交了关于使用 SCUBE3 及其相关分子刺激毛发生长的专利申请。Maksim Plikus 教授也将在自己的实验室及其创立的生物技术公司 Amplifica Holdings Group 进行后续研究。

当然,这项研究成果距离临床应用还有很长的一段路要走,例如:如何克服 Hedgehog 信号通路的致癌效应;SCUBE3 作为一种多功能蛋白,是否会对其他信号通路产生影响,并导致有毒副作用?这些问题仍需慎重考虑。

 

原始出处:

Yingzi Liu, et al. Hedgehog signaling reprograms hair follicle niche fibroblasts to a hyper-activated state. Developmental Cell, 2022.

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    2023-02-20 维他命
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  4. 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  5. 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replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5878, encryptionId=13b658e849, topicName=Dev)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bcaa382, createdName=fzwish20000, createdTime=Mon Aug 29 06:04:29 CST 2022, time=2022-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2094261, encodeId=fef5209426188, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220801/c298eeb2259c4110b14179b97aba2e82/436f77ef216745e49f4d7dbc87ea096e.jpg, createdBy=15fd6475276, createdName=ms5000001410456216, createdTime=Mon Oct 17 16:19:04 CST 2022, time=2022-10-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1231200, encodeId=1987123120092, content=雄脱,毛囊干细胞受真皮乳头成纤维细胞的调节, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1b6c1974111, createdName=huaguang, createdTime=Thu Jul 07 19:53:49 CST 2022, time=2022-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1286430, encodeId=f75c128643073, content=<a href='/topic/show?id=24395268347' target=_blank style='color:#2F92EE;'>#性激素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=52683, encryptionId=24395268347, topicName=性激素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=267e204, createdName=wangyang7958, createdTime=Thu Jul 07 06:04:29 CST 2022, time=2022-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1389139, encodeId=8d67138913925, content=<a href='/topic/show?id=c130636834c' target=_blank style='color:#2F92EE;'>#毛囊#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63683, encryptionId=c130636834c, topicName=毛囊)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca282500032, createdName=1249857fm32暂无昵称, createdTime=Thu Jul 07 06:04:29 CST 2022, time=2022-07-07, status=1, ipAttribution=)]
    2022-10-12 lixiaol
  6. 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    2022-08-29 fzwish20000
  7. 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likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1b6c1974111, createdName=huaguang, createdTime=Thu Jul 07 19:53:49 CST 2022, time=2022-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1286430, encodeId=f75c128643073, content=<a href='/topic/show?id=24395268347' target=_blank style='color:#2F92EE;'>#性激素#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=45, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=52683, encryptionId=24395268347, topicName=性激素)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=267e204, createdName=wangyang7958, createdTime=Thu Jul 07 06:04:29 CST 2022, time=2022-07-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1389139, encodeId=8d67138913925, content=<a href='/topic/show?id=c130636834c' target=_blank style='color:#2F92EE;'>#毛囊#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63683, encryptionId=c130636834c, topicName=毛囊)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca282500032, createdName=1249857fm32暂无昵称, createdTime=Thu Jul 07 06:04:29 CST 2022, time=2022-07-07, status=1, ipAttribution=)]
    2022-10-17 ms5000001410456216

    学习了

    0

  8. 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replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=5878, encryptionId=13b658e849, topicName=Dev)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=bcaa382, createdName=fzwish20000, createdTime=Mon Aug 29 06:04:29 CST 2022, time=2022-08-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2094261, encodeId=fef5209426188, content=学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=34, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20220801/c298eeb2259c4110b14179b97aba2e82/436f77ef216745e49f4d7dbc87ea096e.jpg, createdBy=15fd6475276, createdName=ms5000001410456216, createdTime=Mon Oct 17 16:19:04 CST 2022, time=2022-10-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1231200, encodeId=1987123120092, content=雄脱,毛囊干细胞受真皮乳头成纤维细胞的调节, beContent=null, objectType=article, channel=null, level=null, 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objectType=article, channel=null, level=null, likeNumber=44, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=63683, encryptionId=c130636834c, topicName=毛囊)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=ca282500032, createdName=1249857fm32暂无昵称, createdTime=Thu Jul 07 06:04:29 CST 2022, time=2022-07-07, status=1, ipAttribution=)]
    2022-07-07 huaguang

    雄脱,毛囊干细胞受真皮乳头成纤维细胞的调节

    0

  9. 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  10. 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