Kühn Bernhard, del Monte Federica, Hajjar Roger J, Chang Yuh-Shin, Lebeche Djamel, Arab Shima, Keating Mark T
Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
Nat Med. 2007 Aug;13(8):962-9. doi: 10.1038/nm1619. Epub 2007 Jul 15.
Adult mammalian hearts respond to injury with scar formation and not with cardiomyocyte proliferation, the cellular basis of regeneration. Although cardiogenic progenitor cells may maintain myocardial turnover, they do not give rise to a robust regenerative response. Here we show that extracellular periostin induced reentry of differentiated mammalian cardiomyocytes into the cell cycle. Periostin stimulated mononucleated cardiomyocytes to go through the full mitotic cell cycle. Periostin activated alphaV, beta1, beta3 and beta5 integrins located in the cardiomyocyte cell membrane. Activation of phosphatidylinositol-3-OH kinase was required for periostin-induced reentry of cardiomyocytes into the cell cycle and was sufficient for cell-cycle reentry in the absence of periostin. After myocardial infarction, periostin-induced cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced fibrosis and infarct size, and increased angiogenesis. Thus, periostin and the pathway that it regulates may provide a target for innovative strategies to treat heart failure.
成年哺乳动物心脏对损伤的反应是形成瘢痕，而非通过心肌细胞增殖（即再生的细胞基础）来实现。尽管心脏祖细胞可能维持心肌更新，但它们不会引发强烈的再生反应。在此，我们表明细胞外骨膜蛋白可诱导分化的哺乳动物心肌细胞重新进入细胞周期。骨膜蛋白刺激单核心肌细胞经历完整的有丝分裂细胞周期。骨膜蛋白激活位于心肌细胞膜上的αV、β1、β3和β5整合素。磷脂酰肌醇-3-OH激酶的激活是骨膜蛋白诱导心肌细胞重新进入细胞周期所必需的，并且在没有骨膜蛋白的情况下足以使细胞重新进入细胞周期。心肌梗死后，骨膜蛋白诱导的心肌细胞细胞周期重新进入和有丝分裂与改善心室重构和心肌功能、减少纤维化和梗死面积以及增加血管生成有关。因此，骨膜蛋白及其调节的信号通路可能为治疗心力衰竭的创新策略提供靶点。
