SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability.
SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability.
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DOI：
10.1016/j.stemcr.2014.11.004
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发表时间：
2015-01-13
影响因子：
5.9
通讯作者：
Cho, Hee Cheol
中科院分区：
文献类型：
--
作者：
Ionta, Vittoria;Liang, Wenbin;Kim, Elizabeth H.;Rafie, Reza;Giacomello, Alessandro;Marban, Eduardo;Cho, Hee Cheol
当去除多能性因子时，胚胎干细胞（ESC）经历自发分化，其在其他谱系中也产生心脏亚谱系，包括室心肌细胞和起搏细胞。这种异质性使ESC衍生的心脏细胞在治疗和诊断应用中的使用复杂化。我们试图通过过表达一种对天然心脏起搏器（窦房结）的胚胎模式至关重要的转录因子，来指导ESC特异性分化为心脏起搏器细胞。在ESC分化过程中过表达SHOX 2上调了起搏基因程序，导致体外增强的自律性和体内移植后诱导的生物起搏。增强的自律性伴随着Wnt信号传导的效应子和调节子的时间演变变化。我们的研究结果提供了一种从胚胎干细胞中富集心脏起搏细胞群的策略。SHOX 2在分化的ESC中增强起搏细胞的分子特征SHOX 2增加自发活性心脏衍生物的频率和速率SHOX 2-过表达EB在体内移植时作为生物起搏器起作用Wnt信号传导是SHOX 2-过表达EB的基础。Cho及其同事表明，异源SHOX 2表达通过以下途径促进胚胎干细胞向心脏起搏细胞的分化：增强起搏细胞特异性电生理学。将过表达SHOX 2的胚状体植入大鼠体内心脏产生生物起搏。SHOX 2促进的起搏细胞表型与特异性Wnt调节相关，表明Wnt可能是心脏亚型特异性的谈判者。
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. SHOX2 accentuates the molecular profile of pacemaker cells in differentiating ESCs SHOX2 increases the frequency and rate of spontaneously active cardiac derivatives SHOX2-overexpressing EBs function as biopacemakers when transplanted in vivo Wnt signaling underlies SHOX2-mediated pacemaker cell specification Cho and colleagues show that heterologous SHOX2 expression boosts the differentiation of embryonic stem cells to cardiac pacemaker cells from embryonic stem cells by enhancing pacemaker cell-specific electrophysiology. Implantation of SHOX2-overxpressing embryoid bodies to the rat heart in vivo creates biological pacing. The SHOX2-facilitated pacemaker cell phenotype correlates with specific Wnt modulation, suggesting that Wnt may be a negotiator for cardiac subtype specification.
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