Abstract 18227: Acellular Extracellular Matrix Scaffold Reprograms Cardiac Fibroblasts and Stimulates Adaptive Cardiac Remodeling and Repair

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Abstract

Background: Targeting cardiac fibroblasts may attenuate structural remodeling and progressive loss of cardiac function post-MI. Extracellular matrix (ECM) biomaterials can promote cardiac repair by influencing endogenous cells of the heart via bioactive signaling molecules retained in the scaffolds.

Hypothesis: Cardiac fibroblasts can be reprogrammed towards a pro-reparative phenotype through a specific interaction with bioactive acellular ECM scaffolds.

Methods: Acellular ECM scaffolds were inactivated with 4M guanidine hydrochloride to remove soluble bioactive peptides. Atrial human cardiac fibroblasts (HuCF; n=10) were isolated from patients undergoing cardiac surgery. HuCF were seeded onto bioactive (FGF-2 positive) or inactive (FGF-2 negative) ECM scaffolds overnight. Cells and conditioned media were collected for protein analysis. In vivo, a rat coronary ligation model of MI was used. Bioactive ECM scaffolds were epicardially implanted over completed infarcts and compared against biologically inactive ECM scaffold and sham-treated animals (n=16/group).

Results: Unlike inactivated ECM scaffolds, bioactive ECM scaffolds were shown to release basic fibroblast growth factor (FGF-2) under passive conditions. ECM scaffold inactivation treatment did not negatively affect cell health relative to the bioactive scaffolds (1.9+/-1.4 vs. 1.8+/-0.7 percent apoptosis, p=0.99). HuCF seeded on bioactive scaffolds showed a significant decrease in alpha-SMA expression as compared to inactive scaffolds suggesting attenuated pro-fibrotic activation (0.48+/-0.03 vs. 0.60+/-0.06-fold decrease, p=0.04). HuCF seeded onto bioactive ECM scaffolds assumed a pro-angiogenic state relative to the inactive ECM scaffold group, showing significantly increased expression of FGF-2 (p=0.03), HGF (p=0.01) and VEGF (p=0.01). In vivo, bioactive ECM-treated animals showed significantly attenuated left ventricular dilatation relative to the inactive ECM scaffold group after 14 weeks of treatment (282+/-45 vs. 341+/-58 μL, p=0.03).

Conclusion: Acellular ECM scaffolds attenuate post-MI structural remodeling by reprogramming pro-fibrotic cardiac fibroblasts towards a pro-angiogenic phenotype via FGF-2-dependent signaling.

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