Bio-engineering a Hybrid Material for Heart Regeneration: combining a Synthetic Hydrogel with Fetal Cardiac Extracellular Matrix

PURPOSE
Tissue homeostasis is perturbed by stressful events, which can lead to organ dysfunction and failure. This is particularly true for the heart, where injury resulting from myocardial infarction can result in the loss of functional myocardial tissue and ultimately heart failure. Unlike the adult mammalian heart, the fetal heart has the innate ability for self-repair following injury. This regenerative capacity has been linked to the extracellular matrix (ECM) of the fetal heart. Here we aim to investigate if we can harness the ability of the fetal ECM to guide cardiac repair, thereby setting the stage for next generation regenerative strategies.

METHODS
We utilized transcriptomics to map the ECM composition of the developing murine heart. Candidate fetal ECM components were screened for their ability to induce cardiomyocyte proliferation in vitro. Finally, we bio-engineered a synthetic hydrogel harboring the most promising fetal ECM component and determined its feasibility as a delivery system for future translational application.

RESULTS
We identified 13 cardiac fetal ECM genes, including the well characterized Agrin. As a proof-of-concept, Agrin was incorporated into a variant of the synthetic ureido-pyrimidinone (UPy) hydrogel. Cardiomyocytes cultured on the UPy hydrogel demonstrated increased proliferation as compared to Matrigel coating. Similar results were observed when Glypican-3, a novel fetal cardiac ECM component, was incorporated within the synthetic UPy hydrogel.

DISCUSSION/CONCLUSION
We demonstrate that it is feasible to incorporate fetal ECM components within a synthetic hydrogel and that this hybrid hydrogel induces cardiomyocyte proliferation in vitro, thereby making an important step towards a novel injectable material for therapeutic implementation.