Bulatovic Ivana, Ibarra Cristian, Österholm Cecilia, Wang Heng, Beltrán-Rodríguez Antonio, Varas-Godoy Manuel, Månsson-Broberg Agneta, Uhlén Per, Simon András, Grinnemo Karl-Henrik
Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
PLoS One. 2015 Mar 12;10(3):e0120176. doi: 10.1371/journal.pone.0120176. eCollection 2015.
Generation of new cardiomyocytes is critical for cardiac repair following myocardial injury, but which kind of stimuli is most important for cardiomyocyte regeneration is still unclear. Here we explore if apoptotic stimuli, manifested through caspase activation, influences cardiac progenitor up-regulation and cardiomyocyte differentiation. Using mouse embryonic stem cells as a cellular model, we show that sublethal activation of caspases increases the yield of cardiomyocytes while concurrently promoting the proliferation and differentiation of c-Kit+/α-actininlow cardiac progenitor cells. A broad-spectrum caspase inhibitor blocked these effects. In addition, the caspase inhibitor reversed the mRNA expression of genes expressed in cardiomyocytes and their precursors. Our study demonstrates that sublethal caspase-activation has an important role in cardiomyocyte differentiation and may have significant implications for promoting cardiac regeneration after myocardial injury involving exogenous or endogenous cell sources.
新心肌细胞的生成对于心肌损伤后的心脏修复至关重要，但何种刺激对心肌细胞再生最为重要仍不清楚。在此，我们探究通过半胱天冬酶激活表现出的凋亡刺激是否会影响心脏祖细胞上调和心肌细胞分化。利用小鼠胚胎干细胞作为细胞模型，我们发现半胱天冬酶的亚致死性激活可提高心肌细胞产量，同时促进c-Kit+/α-肌动蛋白低表达心脏祖细胞的增殖和分化。一种广谱半胱天冬酶抑制剂可阻断这些效应。此外，半胱天冬酶抑制剂可逆转心肌细胞及其前体细胞中基因的mRNA表达。我们的研究表明，半胱天冬酶的亚致死性激活在心肌细胞分化中具有重要作用，对于促进涉及外源性或内源性细胞来源的心肌损伤后的心脏再生可能具有重要意义。
