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Down-regulation of Beclin1 promotes direct cardiac reprogramming. Sci Transl Med 2020 Oct 21;12(566)

Date

10/23/2020

Pubmed ID

33087505

Pubmed Central ID

PMC8188650

DOI

10.1126/scitranslmed.aay7856

Scopus ID

2-s2.0-85094173558   18 Citations

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.

Author List

Wang L, Ma H, Huang P, Xie Y, Near D, Wang H, Xu J, Yang Y, Xu Y, Garbutt T, Zhou Y, Liu Z, Yin C, Bressan M, Taylor JM, Liu J, Qian L

Author

Ziqing Liu PhD Assistant Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autophagy
Beclin-1
Cellular Reprogramming
Down-Regulation
Fibroblasts
Mice
Myocytes, Cardiac
Phosphatidylinositol 3-Kinases