Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair

Visual Abstract

Highlights

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  Acellular ECM scaffolds retain bioactive properties capable of stimulating endogenous myocardial repair pathways that could be leveraged therapeutically to promote adaptive cardiac remodeling toward functional recovery after ischemic injury.

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  In rodents with MI, acellular bioactive ECM scaffolds surgically implanted on the epicardium stimulate adaptive cardiac repair and functional recovery with therapeutic effects highly dependent on the bioinductive properties of the biomaterial.

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  Interaction of human cardiac fibroblasts with bioactive ECM scaffolds can induce a robust FGF-dependent cell-mediated vasculogenic paracrine response capable of stimulating functional blood vessel assembly.

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  Acellular bioactive ECM scaffolds surgically implanted on the epicardium post-MI can reprogram resident fibroblasts and stimulate adaptive proreparative pathways enhancing functional recovery.

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  A novel surgical strategy for tissue repair is introduced that can be performed as an adjunct to conventional surgical revascularization with minimal translational challenges.

Summary

Structural cardiac remodeling after ischemic injury can induce a transition to heart failure from progressive loss of cardiac function. Cellular regenerative therapies are promising but face significant translational hurdles. Tissue extracellular matrix (ECM) holds the necessary environmental cues to stimulate cell-based endogenous myocardial repair pathways and promote adaptive remodeling toward functional recovery. Heart epicardium has emerged as an important anatomic niche for endogenous repair pathways including vasculogenesis and cardiogenesis. We show that acellular ECM scaffolds surgically implanted on the epicardium following myocardial infarction (MI) can attenuate structural cardiac remodeling and improve functional recovery. We assessed the efficacy of this strategy on post-MI functional recovery by comparing intact bioactive scaffolds with biologically inactivated ECM scaffolds. We confirm that bioactive properties within the acellular ECM biomaterial are essential for the observed functional benefits. We show that interaction of human cardiac fibroblasts with bioactive ECM can induce a robust cell-mediated vasculogenic paracrine response capable of functional blood vessel assembly. Fibroblast growth factor-2 is uncovered as a critical regulator of this novel bioinductive effect. Acellular bioactive ECM scaffolds surgically implanted on the epicardium post-MI can reprogram resident fibroblasts and stimulate adaptive pro-reparative pathways enhancing functional recovery. We introduce a novel surgical strategy for tissue repair that can be performed as an adjunct to conventional surgical revascularization with minimal translational challenges.