Fibroblast growth factor-2 regulates human cardiac myofibroblast-mediated extracellular matrix remodeling

TLDR

Tissue fibrosis and chamber remodeling are hallmarks of heart failure, driven in part by sustained TGFβ1‑induced activation of cardiac myofibroblasts. The study examined whether low‑molecular‑weight fibroblast growth factor (LMW‑FGF‑2) can mitigate TGFβ1‑induced extracellular matrix dysregulation and remodeling by human cardiac myofibroblasts. Human cardiac myofibroblasts were isolated from surgical biopsies, cultured in type I collagen gels, and exposed to TGFβ1 to induce activation; ECM contraction, remodeling, and apoptosis were quantified with and without LMW‑FGF‑2 using a floating nylon‑grid collagen gel platform and confocal imaging. LMW‑FGF‑2 markedly reduced TGFβ1‑induced myofibroblast activation, ECM contraction, and local remodeling in both ventricular and atrial cells, suggesting it could prevent maladaptive chamber remodeling and fibrosis.

Abstract

Tissue fibrosis and chamber remodeling is a hallmark of the failing heart and the final common pathway for heart failure of diverse etiologies. Sustained elevation of pro-fibrotic cytokine transforming growth factor-beta1 (TGFβ1) induces cardiac myofibroblast-mediated fibrosis and progressive structural tissue remodeling.We examined the effects of low molecular weight fibroblast growth factor (LMW-FGF-2) on human cardiac myofibroblast-mediated extracellular matrix (ECM) dysregulation and remodeling.Human cardiac biopsies were obtained during open-heart surgery and myofibroblasts were isolated, passaged, and seeded within type I collagen matrices. To induce myofibroblast activation and ECM remodeling, myofibroblast-seeded collagen gels were exposed to TGFβ1. The extent of ECM contraction, myofibroblast activation, ECM dysregulation, and cell apoptosis was determined in the presence of LMW-FGF-2 and compared to its absence. Using a novel floating nylon-grid supported thin collagen gel culture platform system, myofibroblast activation and local ECM remodeling around isolated single cells was imaged using confocal microscopy and quantified by image analysis.TGFβ1 induced significant myofibroblast activation and ECM dysregulation as evidenced by collagen gel contraction, structural ECM remodeling, collagen synthesis, ECM degradation, and altered TIMP expression. LMW-FGF-2 significantly attenuated TGFβ1 induced myofibroblast-mediated ECM remodeling. These observations were similar using either ventricular or atrial-derived cardiac myofibroblasts. In addition, for the first time using individual cells, LMW-FGF-2 was observed to attenuate cardiac myofibroblast activation and prevent local cell-mediated ECM perturbations.LMW-FGF-2 attenuates human cardiac myofibroblast-mediated ECM remodeling and may prevent progressive maladaptive chamber remodeling and tissue fibrosis for patients with diverse structural heart diseases.