Research ArticleCARDIAC REGENERATION

Down-regulation of Beclin1 promotes direct cardiac reprogramming

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Science Translational Medicine  21 Oct 2020:
Vol. 12, Issue 566, eaay7856
DOI: 10.1126/scitranslmed.aay7856

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Regulating reprogramming

Reprogramming cardiomyocytes from other cell types could have therapeutic potential for cardiac diseases. Wang et al. studied the induction of cardiomyocytes from murine fibroblasts. They found that autophagy-related 5 (Atg5) regulated autophagy during early cell reprogramming, whereas the autophagic factor Beclin1 inhibited cardiomyocyte induction. In cell and mouse models, the authors showed that loss of Beclin1 resulted in gene expression changes in reprogramming cells, activation of Wnt signaling, and reduction of scar size after myocardial infarction. This study helps identify the roles of autophagy-dependent and -independent signaling pathways in cardiac fate determination.

Abstract

Direct reprogramming of fibroblasts to alternative cell fates by forced expression of transcription factors offers a platform to explore fundamental molecular events governing cell fate identity. The discovery and study of induced cardiomyocytes (iCMs) not only provides alternative therapeutic strategies for heart disease but also sheds lights on basic biology underlying CM fate determination. The iCM field has primarily focused on early transcriptome and epigenome repatterning, whereas little is known about how reprogramming iCMs remodel, erase, and exit the initial fibroblast lineage to acquire final cell identity. Here, we show that autophagy-related 5 (Atg5)–dependent autophagy, an evolutionarily conserved self-digestion process, was induced and required for iCM reprogramming. Unexpectedly, the autophagic factor Beclin1 (Becn1) was found to suppress iCM induction in an autophagy-independent manner. Depletion of Becn1 resulted in improved iCM induction from both murine and human fibroblasts. In a mouse genetic model, Becn1 haploinsufficiency further enhanced reprogramming factor–mediated heart function recovery and scar size reduction after myocardial infarction. Mechanistically, loss of Becn1 up-regulated Lef1 and down-regulated Wnt inhibitors, leading to activation of the canonical Wnt/β-catenin signaling pathway. In addition, Becn1 physically interacts with other classical class III phosphatidylinositol 3-kinase (PI3K III) complex components, the knockdown of which phenocopied Becn1 depletion in cardiac reprogramming. Collectively, our study revealed an inductive role of Atg5-dependent autophagy as well as a previously unrecognized autophagy-independent inhibitory function of Becn1 in iCM reprogramming.

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