Mechanobiology of cardiac regeneration: a molecular approach

Adult heart is one of the least regenerative organs in the human body, with substantial fibrotic scarring in response to tissue damage. In contrast, aquatic salamanders, such as the newt, display unique heart regeneration capacities.

The aim of this proposal is to reveal the physical principles of cell and tissue dynamics that are permissive and instructive for successful regeneration.

I previously discovered that upon injury epicardial progenitors in the newt arrange into a honeycomb-like structure at the lesion site, preceding their differentiation into cardiomyocytes. This arrangement is necessary for regeneration and depends on focal tight junctions. Epicardial progenitors also exist in mammals.

However, upon injury they migrate in isolation and mainly differentiate into fibroblasts, contributing to scar formation.

I hypothesize that cell organization is a key to understand the differences in epicardial cell fate and scar properties.

Here, we will combine tight junction manipulations with state-of-the-art imaging, spatial transcriptomics/proteomics and force measurements to explore how spatial and mechanical cues are harnessed to mediate scarless tissue regeneration.

Furthermore, we will test the functional relevance of collective cell organization utilizing human cardiac organoids as a model.

This study will advance the emergent field of regenerative mechanobiology and inspire the design of mechanotherapeutics to evoke functional regeneration of the mammalian heart.