Overexpression of ERBB4 rejuvenates aged mesenchymal stem cells and enhances angiogenesis via PI3K/AKT and MAPK/ERK pathways

What is it about?

Mesenchymal stem cell (MSC) therapy is promising in treating cardiovascular diseases (CVDs). However, the function of MSC declined with advancing age. Therefore, it is important to rejuvenate of aged MSC without affecting their properties of differentiation. Previous studies suggested ERBB4 might play a role in regulating MSC senescence. In the current study, we aim at investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Our data demonstrated ERBB4 expression declined in aged MSC compared with young MSC. Overexpressing ERBB4 in aged MSC enhanced their resistance to oxidative stress-induced cell death and senescent phenotype, without affecting their differentiation capacity. ERBB4-engineered aged MSC displayed superior cardioprotection after MI, with less apoptosis and enhanced blood vessel density. The pro-angiogenesis effect of ERBB4-engineered MSC was through enhanced secretion of pro-angiogenesis factors including ANG, ENA-78, VEGF, and bFGF. ERBB4 mediated angiogenesis through activating PI3K/AKT and MAPK/ERK signaling pathway, as the impact of ERBB4 on angiogenesis and cytokine secretion was abolished inhibiting the above pathways. Our study demonstrated overexpression of ERBB4 is a novel therapeutic strategy for rejuvenating senescent MSC and promotes the therapeutic effects of aged MSC for CVDs.

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