Establishment of stably expandable induced myogenic stem cells by four transcription factors.
Establishment of stably expandable induced myogenic stem cells by four transcription factors.
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DOI：
10.1038/s41419-018-1114-8
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发表时间：
2018-10-25
影响因子：
9
通讯作者：
Jeong KS
中科院分区：
文献类型：
--
作者：
Lee EJ;Kim M;Kim YD;Chung MJ;Elfadl A;Ulah HMA;Park D;Lee S;Park HS;Kim TH;Hwang D;Jeong KS
通过细胞移植实现健康肌肉的终身再生是退行性肌肉疾病患者的理想治疗方法。然而，从患者身上获得肌肉干细胞是非常有限的，因为他们在疾病状态下已经筋疲力尽。因此，需要开发获得健康肌源性干细胞的方法。在这里，我们发现四种转录因子Six 1，Eya 1，Esrrb和Pax 3将成纤维细胞转化为诱导的肌源性干细胞（iMSC）。iMSCs在体外和体内均表现出向多核肌管的有效分化，并且比肌源性干细胞具有更高的增殖能力。iMSCs传代次数增加，但其增殖能力未丧失。我们进一步分离了CD 106阴性和α7-整合素阳性的iMSC（sort-iMSC），其显示出比iMSC更高的成肌分化能力。此外，对iMSC和sort-iMSC的全基因组转录组分析以及网络分析分别揭示了与iMSC和sort-iMSC的增殖和分化能力增强相关的基因和信号通路。稳定扩增的iMSCs为肌肉萎缩疾病的药物筛选和肌肉再生治疗提供了新的来源。
Life-long regeneration of healthy muscle by cell transplantation is an ideal therapy for patients with degenerative muscle diseases. Yet, obtaining muscle stem cells from patients is very limited due to their exhaustion in disease condition. Thus, development of a method to obtain healthy myogenic stem cells is required. Here, we showed that the four transcription factors, Six1, Eya1, Esrrb, and Pax3, converts fibroblasts into induced myogenic stem cells (iMSCs). The iMSCs showed effective differentiation into multinucleated myotubes and also higher proliferation capacity than muscle derived stem cells both in vitro and in vivo. The iMSCs do not lose their proliferation capacity though the passaging number is increased. We further isolated CD106-negative and α7-integrin-positive iMSCs (sort-iMSCs) showing higher myogenic differentiation capacity than iMSCs. Moreover, genome-wide transcriptomic analysis of iMSCs and sort-iMSCs, followed by network analysis, revealed the genes and signaling pathways associated with enhanced proliferation and differentiation capacity of iMSCs and sort-iMSCs, respectively. The stably expandable iMSCs provide a new source for drug screening and muscle regenerative therapy for muscle wasting disease.
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