Abstract 548: Cellular Contributions to Neonatal Cardiac Regeneration

Abstract

While the neonatal mouse heart possesses a remarkable ability to regenerate up to a week after birth, the adult mammalian heart is susceptible to irreversible scar formation that impedes cardiac function. Such a scar is formed by the precocious deposition of extracellular matrix (ECM) by resident cardiac fibroblasts (CFs). Unlike their adult counterparts, neonatal CFs in the regenerative widow may have a unique phenotype that contributes to cardiac regeneration and scar resolution. Indeed, the neonatal cardiac ECM secreted by CFs is reported to stimulate regeneration, yet the underlying mechanisms of CF-mediated cardiac repair in the neonate has not been examined. Here, we present a strategy to establish the role of tissue resident CFs in mouse neonatal cardiac regeneration through selective cell depletion and RNA sequencing. Through the initial analysis of published RNA sequencing data, we identified an enrichment of pro-regenerative molecules such as amphiregulin (Areg) during the neonatal regenerative window. Areg, an epidermal growth factor ligand, has been shown to paradoxically stimulate both cardiac repair and pathological fibrosis after adult cardiac injury. To assess its impact on the neonatal cardiac injury response, we developed an adeno-associated virus serotype 9 with the complete coding sequence of mouse Areg (AAV9:Areg) controlled by the cardiomyocyte-specific cardiac troponin T promoter. In vivo , AAV9:Areg treated mice accumulate BrdU+ (proliferative) non-myocytes adjacent to Areg-expressing cardiomyocytes. Ongoing studies are aimed at evaluating the contribution of CFs to neonatal cardiac repair, including whether Areg-dependent cellular changes impact CFs in the neonatal regenerative window in a manner distinct from that in the adult injury response.