Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA; Sapienza University of Rome, Rome 00161, Italy.
Cedars-Sinai Heart Institute, Los Angeles, CA 90048, USA.
Stem Cell Reports. 2015 Jan 13;4(1):129-142. doi: 10.1016/j.stemcr.2014.11.004. Epub 2014 Dec 18.
When pluripotency factors are removed, embryonic stem cells (ESCs) undergo spontaneous differentiation, which, among other lineages, also gives rise to cardiac sublineages, including chamber cardiomyocytes and pacemaker cells. Such heterogeneity complicates the use of ESC-derived heart cells in therapeutic and diagnostic applications. We sought to direct ESCs to differentiate specifically into cardiac pacemaker cells by overexpressing a transcription factor critical for embryonic patterning of the native cardiac pacemaker (the sinoatrial node). Overexpression of SHOX2 during ESC differentiation upregulated the pacemaker gene program, resulting in enhanced automaticity in vitro and induced biological pacing upon transplantation in vivo. The accentuated automaticity is accompanied by temporally evolving changes in the effectors and regulators of Wnt signaling. Our findings provide a strategy for enriching the cardiac pacemaker cell population from ESCs.
当多能性因子被去除时，胚胎干细胞（ESCs）会自发分化，其中也会产生包括心室肌细胞和起搏细胞在内的心脏亚群。这种异质性使得 ESC 衍生的心脏细胞在治疗和诊断应用中变得复杂。我们试图通过过表达对于天然心脏起搏器（窦房结）胚胎模式形成至关重要的转录因子来指导 ESC 特异性分化为心脏起搏细胞。在 ESC 分化过程中过表达 SHOX2 会上调起搏基因程序，导致体外自动性增强，并在体内移植后诱导生物起搏。增强的自动性伴随着 Wnt 信号效应物和调节剂的时间演变变化。我们的研究结果为从 ESCs 中富集心脏起搏细胞提供了一种策略。
