Defining the Unique Role of Fibroblasts in Neonatal Cardiac Regeneration
Description: Adult mammalian hearts lack the capacity to regenerate. Since mature (adult) cardiomyocytes (CMs; cardiac muscle cells) are post-mitotic, the fibrotic scar formed by cardiac fibroblasts (CFs) after a myocardial infarction is irreversible. This scar often contributes to left ventricular dysfunction and heart failure, the leading causes of death in US. Recent studies have revealed a remarkable ability of neonatal hearts to regenerate up to a week post birth. Transient fibrosis during regeneration has been marked in mouse models but only studied in zebrafish models. This proposal aims to fill this gap in knowledge. Neonatal CFs in the regenerative widow may have a unique phenotype that contributes specifically to cardiac regeneration. Indeed, the neonatal cardiac extracellular matrix formed by CFs has been reported to stimulate regeneration and prevent adverse repair. Even cytokines from CFs have been shown to stimulate CM proliferation. In this study, I will establish the role of tissue resident CFs in mouse neonatal cardiac regeneration (Aim 1) through selective cell depletion and RNA sequencing of CFs. Since the discovery of a reliable mammalian model for cardiac regeneration, there have been numerous studies on the effect of pro-regenerative molecules on cardiac healing. Analysis of published RNA sequencing data revealed an enrichment of pro-regenerative molecules such as amphiregulin (Areg) during this 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. By examining the impact of Areg on the neonatal regenerative window, I will assess its role on CF plasticity (Aim 2). Understanding the unique responses of neonatal CFs and their responses to pro-regenerative cues such as Areg will reveal novel therapeutic targets for cardiac repair in adult cardiac injury.
Funder: American Heart Association
Amount: $62,030
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2020-01-01
End date: 2020-08-31
Investigators: Adwiteeya Misra, Adwiteeya Misra
Institution: University of Rochester Medical Center
Funded outputs count: 2
Funder award ID: 20PRE35210597
OpenAlex ID: G5061035644