Conversion of human fibroblasts into functional cardiomyocytes by small molecules
Conversion of human fibroblasts into functional cardiomyocytes by small molecules
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DOI：
10.1126/science.aaf1502
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发表时间：
2016-06-03
期刊：
影响因子：
56.9
通讯作者：
Ding, Sheng
中科院分区：
文献类型：
--
作者：
Cao, Nan;Huang, Yu;Ding, Sheng
将体细胞成纤维细胞重编程为其他谱系将为再生治疗提供一种有前景的细胞来源。然而，将人类细胞转分化为特定的同质、功能性细胞类型具有挑战性。在此我们表明，通过用我们称之为9C的九种化合物组合处理人类成纤维细胞，可以产生类心肌细胞。化学诱导的类心肌细胞均匀收缩，并且在转录组、表观遗传学和电生理特性方面类似于人类心肌细胞。用9C处理人类成纤维细胞导致关键心脏发育基因处的染色质构象更加开放，使其启动子和增强子能够结合主要心肌生成信号的效应物。当移植到梗死小鼠心脏中时，经9C处理的成纤维细胞有效地转化为化学诱导的类心肌细胞。这种针对谱系特异性重编程的药理学方法在进一步优化以产生成熟心脏细胞后可能具有许多重要的治疗意义。
Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells into specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds that we term 9C. The chemically induced cardiomyocyte-like cells uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters and enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to chemically induced cardiomyocyte-like cells. This pharmacological approach to lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.