Recapitulating Electrical, Mechanical and Extracellular-matrix cues via Multifunctional Biomaterials to Engineer Regeneration of cardiac tissue

Heart attacks lead to the death of functional cardiomyocytes in heart muscle which cannot be replaced. Every sixth man and seventh woman will die from a heart attack or complications following, and there is no cure to replace this cardiac tissue. Although stem cells can be differentiated into precardiomyocytes they pose an oncogenic risk due to their pluripotency. More recently transdifferentiation has emerged as a process of directly reprogramming one cell type into another but has, to date, quite a low efficiency in generating cardiomyocytes.

Transdifferentiation in vivo, however, has had markedly more success, most likely as cells are exposed to a unique environment defined by the local extracellular matrix (ECM), dynamic mechanical forces via the beating of the heart and electrical action potentials being generated by the heart’s electrical conduction system.

The current state-of-the-art has focused only on 2D approaches; delivering cardiac transcription factors and growth factors alone.. This proposal is a unique engineering approach to recapitulate a cardioinductive platform based on mechanical, electrical and ECM cues to generate cardiomyocytes in high numbers from transdifferentiating fibroblasts.

This research will form the basis towards generating three substantial outcomes: a cardioinductive biomaterial gene delivery system to transdifferentiate fibroblasts within the infarcted myocardium, efficiently transdifferentiate cardiomyocytes in vitro towards creating functional ‘disease-in-a-dish models’ and finally to generate mature cardiomyocytes suitable for transplantation. These advances will not only improve quality of life for the patient but provide tools to study disease and perform pharmaceutical research.