Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells.
Ex Vivo Expansion and In Vivo Self-Renewal of Human Muscle Stem Cells.
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体内扩张和体内自我更新人类肌肉干细胞。
DOI：
10.1016/j.stemcr.2015.08.004
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发表时间：
2015-10-13
影响因子：
5.9
通讯作者：
Rando TA
中科院分区：
文献类型：
--
作者：
Charville GW;Cheung TH;Yoo B;Santos PJ;Lee GK;Shrager JB;Rando TA
成体骨骼肌干细胞，或卫星细胞（SC），移植到受伤或患病组织后再生功能性肌肉。为了深入了解人类SC（huSC）生物学，我们通过前瞻性分离的静止和活化huSC的RNA测序分析了转录组动态。该分析表明，当离体维持在高有丝分裂原条件下时，huSC分化并失去增殖潜力。基因表达的进一步分析显示，p38 MAPK在huSC自我更新的转录网络中起作用。p38信号传导的激活与huSC分化相关，而p38的抑制可逆地阻止分化，使得huSC能够扩增。当移植时，扩增的huSC分化以产生嵌合肌肉，并以比新鲜分离的细胞或在没有p38抑制的情况下培养的细胞更高的频率作为SC移植到亚层龛中。这些研究表明huSC转录组的特征，其促进离体扩增以允许增强自我更新huSC的限定群体的功能性植入。从不同肌肉中前瞻性分离高纯度的huSC用于研究huSC转录组的RNA测序资源huSC分化的核心转录因子调控网络扩增的可遗传操纵和体内自我更新的huSC在这篇文章中，Rando和同事使用RNA测序和细胞移植纯化和研究人骨骼肌干细胞。他们表明，p38 MAPK信号传导对于人肌肉干细胞分化是重要的，并且p38的药理学抑制使得能够在移植后扩增能够自我更新的肌肉干细胞。
Adult skeletal muscle stem cells, or satellite cells (SCs), regenerate functional muscle following transplantation into injured or diseased tissue. To gain insight into human SC (huSC) biology, we analyzed transcriptome dynamics by RNA sequencing of prospectively isolated quiescent and activated huSCs. This analysis indicated that huSCs differentiate and lose proliferative potential when maintained in high-mitogen conditions ex vivo. Further analysis of gene expression revealed that p38 MAPK acts in a transcriptional network underlying huSC self-renewal. Activation of p38 signaling correlated with huSC differentiation, while inhibition of p38 reversibly prevented differentiation, enabling expansion of huSCs. When transplanted, expanded huSCs differentiated to generate chimeric muscle and engrafted as SCs in the sublaminar niche with a greater frequency than freshly isolated cells or cells cultured without p38 inhibition. These studies indicate characteristics of the huSC transcriptome that promote expansion ex vivo to allow enhanced functional engraftment of a defined population of self-renewing huSCs. Prospective isolation of highly pure huSCs from diverse muscles RNA sequencing resource for studying the huSC transcriptome Core transcription factor regulatory network of huSC differentiation Expanded huSCs that are genetically manipulable and self-renew in vivo In this article, Rando and colleagues purify and study human skeletal muscle stem cells using RNA sequencing and cell transplantation. They show that p38 MAPK signaling is important for human muscle stem cell differentiation and that pharmacologic inhibition of p38 enables expansion of muscle stem cells capable of self-renewing after transplantation.