Ahmad Waqas, Dutta Suchandrima, He Xingyu, Chen Sophie, Saleem Muhammad Zubair, Wang Yigang, Liang Jialiang
Department of Pathology and Laboratory Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
Bioengineering (Basel). 2025 Aug 30;12(9):940. doi: 10.3390/bioengineering12090940.
Myocardial infarction-induced cardiovascular diseases remain a leading cause of mortality worldwide. Excessive post-infarct fibrosis contributes to adverse cardiac remodeling and the progression to heart failure. In vivo reprogramming strategies offer a promising avenue for heart regeneration by directly converting resident fibroblasts into cardiomyocytes through enforced expression of cardiogenic genes. This approach circumvents the need for invasive biopsies, cell expansion, induction of pluripotency, or autologous transplantation. Despite these advantages, key challenges persist, including low reprogramming efficiency and limited cellular targeting specificity. A critical factor for effective anti-fibrotic therapy is the precise and efficient delivery of reprogramming effectors specifically to fibrotic fibroblasts, while minimizing off-target effects on non-fibroblast cardiac cells and fibroblasts in non-cardiac tissues. In this review, we discuss the cellular and molecular mechanisms underlying in vivo cardiac reprogramming, with a focus on fibroblast heterogeneity, key transcriptional drivers, and relevant intercellular interactions. We also examine current advances in fibroblast-specific delivery systems employing both viral and non-viral vectors for the administration of lineage-reprogramming factors such as cDNA overexpressions or microRNAs. Finally, we underscore innovative strategies that hold promise for enhancing the precision and efficacy of cellular reprogramming, ultimately fostering translational development and paving the way for rigorous preclinical assessment.
心肌梗死引发的心血管疾病仍是全球主要的死亡原因。梗死后过度纤维化会导致不良的心脏重塑并促使病情发展为心力衰竭。体内重编程策略为心脏再生提供了一条有前景的途径，即通过强制表达心脏发生基因将驻留成纤维细胞直接转化为心肌细胞。这种方法无需进行侵入性活检、细胞扩增、诱导多能性或自体移植。尽管有这些优势，但关键挑战依然存在，包括重编程效率低和细胞靶向特异性有限。有效抗纤维化治疗的一个关键因素是将重编程效应物精确且高效地特异性递送至纤维化的成纤维细胞，同时将对非成纤维细胞心脏细胞和非心脏组织中成纤维细胞的脱靶效应降至最低。在本综述中，我们讨论了体内心脏重编程的细胞和分子机制，重点关注成纤维细胞异质性、关键转录驱动因子以及相关的细胞间相互作用。我们还研究了目前在使用病毒和非病毒载体的成纤维细胞特异性递送系统方面取得的进展，这些系统用于递送谱系重编程因子，如cDNA过表达或微小RNA。最后，我们强调了一些创新策略，这些策略有望提高细胞重编程的精准性和有效性，最终推动转化研究发展并为严格的临床前评估铺平道路。
