Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair

Holly E M Mewhort; Daniyil A Svystonyuk; Jeannine D Turnbull; Guoqi Teng; Darrell D Belke; David G Guzzardi; Daniel S Park; Sean Kang; Morley D Hollenberg; Paul W M Fedak

doi:10.1016/j.jacbts.2017.05.005

Bioactive Extracellular Matrix Scaffold Promotes Adaptive Cardiac Remodeling and Repair

JACC Basic Transl Sci. 2017 Aug 18;2(4):450-464. doi: 10.1016/j.jacbts.2017.05.005. eCollection 2017 Aug.

Affiliations

¹ Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
² Department of Physiology and Pharmacology, Department of Medicine, Cumming School of Medicine, Snyder Institute for Chronic Disease, University of Calgary, Calgary, Alberta, Canada.

Abstract

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.

Keywords: ANOVA, analysis of variance; ECM, extracellular matrix; EF, ejection fraction; EMT, epithelial-to-mesenchymal transition; FGF, fibroblast growth factor; HGF, hepatocyte growth factor; HUVEC, human umbilical vein endothelial cell; LV, left ventricle; MI, myocardial infarction; SIS-ECM, small intestinal submucosal extracellular matrix; VEGF, vascular endothelial growth factor; extracellular matrix; regeneration; vasculogenesis.