Ischemic heart disease is the leading cause of morbidity, mortality, and healthcare expenditure worldwide due to an inability of the heart to regenerate following injury. Thus, novel heart failure therapies aimed at promoting cardiomyocyte regeneration are desperately needed. In recent years, direct reprogramming of resident cardiac fibroblasts to induced cardiac-like myocytes (iCMs) has emerged as a promising therapeutic strategy to repurpose the fibrotic response of the injured heart toward a functional myocardium. Direct cardiac reprogramming was initially achieved through the overexpression of the transcription factors (TFs) Gata4, Mef2c, and Tbx5 (GMT). However, this combination of TFs and other subsequent cocktails demonstrated limited success in reprogramming adult human and mouse fibroblasts, constraining the clinical translation of this therapy. Over the past decade, significant effort has been dedicated to optimizing reprogramming cocktails comprised of cardiac TFs, epigenetic factors, microRNAs, or small molecules to yield efficient cardiac cell fate conversion. Yet, efficient reprogramming of adult human fibroblasts remains a significant challenge. Underlying mechanisms identified to accelerate this process have been centered on epigenetic remodeling at cardiac gene regulatory regions. Further studies to achieve a refined understanding and directed means of overcoming epigenetic barriers are merited to more rapidly translate these promising therapies to the clinic.

由于心脏在受伤后无法再生，缺血性心脏病是全球发病率、死亡率和医疗保健支出的主要原因。因此，迫切需要旨在促进心肌细胞再生的新型心力衰竭疗法。近年来，将常驻心脏成纤维细胞直接重编程为诱导心脏样肌细胞 (iCM) 已成为一种有前途的治疗策略，可将受伤心脏的纤维化反应重新用于功能性心肌。直接心脏重编程最初是通过转录因子 (TF) Gata4、Mef2c 和 Tbx5 (GMT) 的过表达实现的。然而，这种 TFs 和其他后续鸡尾酒的组合在重新编程成人和小鼠成纤维细胞方面表现出有限的成功，限制了这种疗法的临床转化。在过去的十年中，人们致力于优化由心脏 TF、表观遗传因子、microRNA 或小分子组成的重编程混合物，以产生有效的心脏细胞命运转换。然而，成人成纤维细胞的有效重编程仍然是一项重大挑战。确定加速这一过程的潜在机制集中在心脏基因调控区的表观遗传重塑。值得进一步研究以实现对克服表观遗传障碍的精确理解和定向方法，以更快地将这些有希望的疗法转化为临床。或小分子以产生有效的心脏细胞命运转换。然而，成人成纤维细胞的有效重编程仍然是一项重大挑战。确定加速这一过程的潜在机制集中在心脏基因调控区的表观遗传重塑。值得进一步研究以实现对克服表观遗传障碍的精确理解和定向方法，以更快地将这些有希望的疗法转化为临床。或小分子以产生有效的心脏细胞命运转换。然而，成人成纤维细胞的有效重编程仍然是一项重大挑战。确定加速这一过程的潜在机制集中在心脏基因调控区的表观遗传重塑。值得进一步研究以实现对克服表观遗传障碍的精确理解和定向方法，以更快地将这些有希望的疗法转化为临床。