THE ROLE OF THE ERBB SIGNALING PATHWAY IN CARDIOVASCULAR PROGENITOR CELL-BASED REPAIR
Adult mammalian hearts lack self-renewal and proliferative capabilities necessary for cardiovascular regeneration. Current treatments using cardiac progenitor cells (CPCs) for cell-based repair do not restore cardiac function in patients who experience a myocardial infarction (MI). Our laboratory has been studying Islet-1+ neonatal CPCs as a promising candidate for cell-based repair due to their ability to significantly improve cardiac function after MI in sheep. The current study addresses the hypothesis that the ERBB pathway is linked to the Hippo-pathway to activate YAP1 by the involvement of an autocrine loop that upregulates neuregulin (NRG). In our sheep model of MI and cardiovascular progenitor cell-based repair, tissue sections from the infarct zone of three neonatal Islet-1+ CPC treated sheep and corresponding control cardiac tissue sections were used to extract RNA, prepare cDNA and perform RT-qPCR to quantify transcripts associated with the NRG-ERBB signaling pathway. Induced levels of NRG1 and NRG2 were identified in the cardiovascular repair zone of Islet-1+ CPC treated infarcted sheep. ERBB receptors 1-4 and PIK3C2B levels were induced following cell-based treatment. In addition, RT-qPCR and western blot experiments were done on human neonatal Islet-1+ CPCs treated with and without Wnt5a to investigate transcripts associated with the ERBB pathway and YAP1 protein expression. We showed an increase in the expression of NRG1, ERBB3, PIK3CD, and YAP1 after 72 hrs of Wnt5a treatment along with overexpression of YAP1 protein at 144 hrs following Wnt5a treatment. Our studies provide new insight into the mechanism by which ERBB signaling contributes to Islet-1+ cell-based repair.