直接心脏重编程:基础生物学和临床应用中的进展和挑战。

Direct cardiac reprogramming: progress and challenges in basic biology and clinical applications.

机构信息

From the Department of Cardiology, Keio University School of Medicine, Japan Science and Technology CREST, Tokyo, Japan (T.S., M.I.); Japan Science and Technology CREST, Tokyo, Japan (M.I.); Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan (S.Y.); and Gladstone Institute of Cardiovascular Disease, San Francisco, CA (S.Y.).

出版信息

Circ Res. 2015 Apr 10;116(8):1378-91. doi: 10.1161/CIRCRESAHA.116.305374.

Abstract

The discovery of induced pluripotent stem cells changed the field of regenerative medicine and inspired the technological development of direct reprogramming or the process by which one cell type is directly converted into another without reverting a stem cell state by overexpressing lineage-specific factors. Indeed, direct reprogramming has proven sufficient in yielding a diverse range of cell types from fibroblasts, including neurons, cardiomyocytes, endothelial cells, hematopoietic stem/progenitor cells, and hepatocytes. These studies revealed that somatic cells are more plastic than anticipated, and that transcription factors, microRNAs, epigenetic factors, secreted molecules, as well as the cellular microenvironment are all important for cell fate specification. With respect to the field of cardiology, the cardiac reprogramming presents as a novel method to regenerate damaged myocardium by directly converting endogenous cardiac fibroblasts into induced cardiomyocyte-like cells in situ. The first in vivo cardiac reprogramming reports were promising to repair infarcted hearts; however, the low induction efficiency of fully reprogrammed, functional induced cardiomyocyte-like cells has become a major challenge and hampered our understanding of the reprogramming process. Nevertheless, recent studies have identified several critical factors that may affect the efficiency and quality of cardiac induction and have provided new insights into the mechanisms of cardiac reprogramming. Here, we review the progress in direct reprogramming research and discuss the perspectives and challenges of this nascent technology in basic biology and clinical applications.

摘要

诱导多能干细胞的发现改变了再生医学领域,并激发了直接重编程技术的发展,即通过过表达谱系特异性因子将一种细胞类型直接转化为另一种细胞类型,而无需逆转干细胞状态。事实上,直接重编程已经被证明足以从成纤维细胞中产生多种类型的细胞,包括神经元、心肌细胞、内皮细胞、造血干/祖细胞和肝细胞。这些研究表明,体细胞比预期的更具可塑性,转录因子、microRNAs、表观遗传因子、分泌分子以及细胞微环境对于细胞命运特化都很重要。就心脏病学领域而言,心脏重编程是一种通过直接将内源性心肌成纤维细胞转化为诱导性心肌细胞样细胞来再生受损心肌的新方法。最初的体内心脏重编程报告令人鼓舞,可以修复梗死的心脏;然而,完全重编程的、功能性的诱导性心肌细胞样细胞的低诱导效率已成为一个主要挑战,阻碍了我们对重编程过程的理解。尽管如此,最近的研究已经确定了几个可能影响心脏诱导效率和质量的关键因素,并为心脏重编程的机制提供了新的见解。在这里,我们综述了直接重编程研究的进展,并讨论了这项新兴技术在基础生物学和临床应用中的前景和挑战。

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