Mesenchymal stem cell (MSC) transplantation has achieved only modest success in the treatment of ischemic heart disease owing to poor cell viability in the diseased microenvironment. Activation of the NRG1 (neuregulin1)-ERBB4 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 4) signaling pathway has been shown to stimulate mature cardiomyocyte cell cycle re-entry and cell division. In this connection, we aimed to determine whether overexpression of ERBB4 in MSCs can enhance their cardio-protective effects following myocardial infarction. NRG1, MSCs or MSC-ERBB4 (MSC with ERBB4 overexpression), were transplanted into mice following myocardial infarction. Superior to that of MSCs and solely NRG1, MSC-ERBB4 transplantation significantly preserved heart functions accompanied with reduced infarct size, enhanced cardiomyocyte division and less apoptosis during early phase of infarction. The transduction of ERBB4 into MSCs indeed increased cell mobility and apoptotic resistance under hypoxic and glucose-deprived conditions via a PI3K/Akt signaling pathway in the presence of NRG1. Unexpectedly, introduction of ERBB4 into MSC in turn potentiates NRG1 synthesis and secretion, thus forming a novel NRG1-ERBB4-NRG1 autocrine loop. Conditioned medium of MSC-ERBB4 containing elevated NRG1, promoted cardiomyocyte growth and division, whereas neutralization of NRG1 blunted this proliferation. These findings collectively suggest that ERBB4 overexpression potentiates MSC survival in the infarcted heart, enhances NRG1 generation to restore declining NRG1 in the infarcted region and stimulates cardiomyocyte division. ERBB4 has an important role in MSC-mediated myocardial repairs.
