Department of Medicine, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA; Vanderbilt Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, USA.
Program in Molecular, Cellular, Developmental Biology, and Genetics, University of Minnesota, Minneapolis, MN, USA.
Stem Cell Reports. 2022 Jul 12;17(7):1604-1619. doi: 10.1016/j.stemcr.2022.05.004. Epub 2022 Jun 9.
Fibroblasts can be reprogrammed into induced cardiomyocyte-like cells (iCMs) by forced expression of cardiogenic transcription factors. However, it remains unknown how fibroblasts adopt a cardiomyocyte (CM) fate during their spontaneous ongoing transdifferentiation toward myofibroblasts (MFs). By tracing fibroblast lineages following cardiac reprogramming in vitro, we found that most mature iCMs are derived directly from fibroblasts without transition through the MF state. This direct conversion is attributable to mutually exclusive induction of cardiac sarcomeres and MF cytoskeletal structures in the cytoplasm of fibroblasts during reprogramming. For direct fate switch from fibroblasts to iCMs, significant remodeling of actin isoforms occurs in fibroblasts, including induction of α-cardiac actin and decrease of the actin isoforms predominant in MFs. Accordingly, genetic or pharmacological ablation of MF-enriched actin isoforms significantly enhances cardiac reprogramming. Our results demonstrate that remodeling of actin isoforms is required for fibroblast to CM fate conversion by cardiac reprogramming.
成纤维细胞可以通过强制表达心脏发生转录因子重编程为诱导心肌细胞样细胞（iCM）。然而，成纤维细胞在自发向肌成纤维细胞（MF）转化过程中如何获得心肌细胞（CM）命运仍然未知。通过在体外心脏重编程后追踪成纤维细胞谱系，我们发现大多数成熟的 iCM 直接来源于成纤维细胞，而无需经过 MF 状态的过渡。这种直接转化归因于在重编程过程中细胞质中成纤维细胞中心肌肌节和 MF 细胞骨架结构的相互排斥诱导。为了实现成纤维细胞向 iCM 的直接命运转换，成纤维细胞中的肌动蛋白同工型发生显著重塑，包括诱导α-心脏肌动蛋白和降低 MF 中主要的肌动蛋白同工型。因此，MF 富含的肌动蛋白同工型的遗传或药理学消融显著增强了心脏重编程。我们的结果表明，肌动蛋白同工型的重塑对于心脏重编程中成纤维细胞向 CM 命运的转换是必需的。
