The transcriptional regulation of cardiomyocyte polyploidization and its relevance in cardiac regeneration

Introduction

The mammalian heart is a non-regenerative organ due to the extremely limited ability of fully differentiated cardiomyocytes (CMs) to proliferate. While neonatal hearts still contain mostly diploid CMs and regenerate efficiently, physiological postnatal CM polyploidization/hypertrophy ensures the contractile capacity of the adult myocardium but represents a roadblock to cardiac regeneration.

Problem Statement

Due to this limitation, diseases that provoke CM loss, like acute ischemia, frequently lead to heart failure.

Project Overview

REACTIVA will establish a new strategy for heart regeneration based on the reactivation of a dormant endogenous mechanism, thereby achieving unprecedented advances in the field of cardiac regenerative biology.

Research Findings

In mice, the proportion of adult diploid CMs (ADCs) correlates with regenerative ability. However, efforts to identify a molecular signature for ADCs have been unsuccessful, which has precluded exploring their roles in heart regeneration.

Using an improved methodology for single-CM RNAseq, my group has identified a molecular signature of ADCs related to the fetal program and controlled by a single repressor transcription factor. This factor is specifically expressed in the polyploid CM population (PCM) and its inhibition in the postnatal mouse heart robustly increases ADC abundance and proliferative activity.

Hypothesis

Based on these findings, we propose that ADCs underlie a vestigial endogenous mechanism for adult mammalian heart renewal and that their stimulation will promote heart regeneration.

Objectives

REACTIVA will exploit our new findings on ADCs to:

1. Fully characterize the ADC regulatory network, identifying factors to modulate it.
2. Identify and trace ADCs in the adult heart, defining their niches and contribution to renew and expand the CM population during heart homeostasis, aging, and disease.
3. Use the generated knowledge to induce ADC activation with the goal of promoting adult mammalian heart regeneration.