期刊
STEM CELL REPORTS
卷 17, 期 7, 页码 1604-1619出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2022.05.004
关键词
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资金
- Vanderbilt Institute of Chemical Biology
- Vanderbilt-Ingram Cancer Center [P30 CA68485]
- Gilead Sciences Research Scholars Program
- NIH [R01 AR049899, R01 HL146524]
- AHA [20POST35210170]
By tracing fibroblast lineages following cardiac reprogramming in vitro, it has been found that most mature iCMs are derived directly from fibroblasts, without transitioning through the MF state. This direct conversion is due to mutually exclusive induction of cardiac sarcomeres and MF cytoskeletal structures in the cytoplasm of fibroblasts during reprogramming.
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 alpha-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.
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