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

The age-related functional exhaustion limits potential efficacy of mesenchymal stem cell (MSC) in treating cardiovascular disease. Therefore, rejuvenation of aged MSC in the elderly population is of great interest. We have previously reported that Erb-B2 receptor tyrosine kinase 4 (ERBB4) plays a critical role in regulating MSC survival under hypoxia. The aim of this study was to investigate whether ERBB4 rejuvenates aged MSC and how ERBB4 enhances therapeutic efficacy of aged MSC in treating myocardial infarction (MI). Compared with vector aged MSC (aged-MSC), ERBB4-engineered aged MSC (ER4-aged-MSC) conferred resistance to oxidative stress-induced cell death and ameliorated the senescent phenotype in vitro. Four weeks after MI, the ER4-aged-MSC group exhibited enhanced blood vessel density, reduced cardiac remodeling and apoptosis with improved heart function compared with the aged-MSC group. Overexpression of ERBB4 caused an increase in phosphorylated v-akt murine thymoma viral oncogene homolog 1 (AKT)...