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Beclin1 Deficiency Unlocks Cardiac Lineage Commitment through Convergent Wnt and BMP Signaling Activation

ABSTRACT: Beclin1 plays significant roles in cardiac organogenesis. Beclin1 can regulate the fate conversion of fibroblasts into cardiomyocytes. However, the function and mechanism of Beclin1 in regulating early cardiac lineage commitment and differentiation remain unclear. To explore its potential role in cardiac lineage development, we utilized model of cardiomyocyte differentiation from mouse embryonic stem cells (mESCs) to simulate early cardiogenesis and investigated the function of Beclin1. We show that the knockdown of Beclin1 facilitates cardiomyocyte differentiation. Through bulk RNA-sequencing analysis, we found that knocking down Beclin1 activated the Wnt signaling pathway at the embryoid body stage but inhibited its activity at the cardiomyocyte stage. Moreover, the Bone morphogenetic protein (Bmp) signaling pathway was continuously activated throughout cardiomyocyte differentiation process. Our findings demonstrate a novel function of Beclin1 during cardiac differentiation. The activation of Wnt-mediated Bmp signaling pathway represents a major mechanism by which the deficiency of Beclin1 promotes mESCs differentiation into cardiomyocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE293719 | GEO | 2025/12/04

REPOSITORIES: GEO

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Project description:Cardiovascular diseases are a major cause of life-threatening burden around the world. The heart has a very low regeneration capacity and donor organs for transplantation are scarce. Therefore regeneration of lost myocardium with stem cell-derived cardiomyocytes (CMs) provides an attractive strategy for heart repair. Human pluripotent stem cells (hPSCs) can be efficiently differentiated in vitro into CMs but the molecular mechanisms behind this process are still not fully understood. In particular identification of secreted autocrine and/or paracrine factors that function as important extrinsic signals remained elusive because the mass spectrometry (MS)-based identification of secreted proteins from cell culture supernatants is impeded by high levels of albumin present in common differentiation media. Thus we established an albumin-free cardiomyogenic differentiation medium and performed secretomics at seven different time points during in vitro differentiation. This analysis led to the identification of 4832 proteins with 1802 being significantly altered during differentiation and 431 of these were annotated as secreted according to gene ontology. Bioinformatics revealed enrichment of extrinsic Wnt pathway-related proteins 3 days upon induction of differentiation and of extracellular matrix proteins in the resulting CMs. Numerous extrinsic components of Wnt, Activin A, Nodal, TGFβ, BMP or FGF signaling pathways were quantitatively assessed during differentiation. Notably, the abundance of pathway agonists was generally lower compared to the respective antagonists but their curves of progression over timer were rather similar. We hypothesize that Activin A, Nodal and TGFβ signaling are turned down shortly upon initiation of cardiac differentiation whereas BMP signaling is switched on. Wnt and FGF signaling peaks between d0 and d3 of differentiation and interestingly, Activin A and TGFβ signaling seem to be reactivated at the cardiac progenitor stages and/or in early CMs.

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Beclin1 Deficiency Unlocks Cardiac Lineage Commitment through Convergent Wnt and BMP Signaling Activation

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