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

• Published in: Journal of translational medicine Vol. 13; no. 1; p. 147
• Main Authors: Svystonyuk, Daniyil A, Ngu, Janet M C, Mewhort, Holly E M, Lipon, Brodie D, Teng, Guoqi, Guzzardi, David G, Malik, Getanshu, Belke, Darrell D, Fedak, Paul W M
• Format: Journal Article
• Language: English
• Published: England BioMed Central 07.05.2015
• Subjects: Apoptosis; Biopsy; Cell Differentiation; Collagen - metabolism; Extracellular Matrix - metabolism; Female; Fibroblast Growth Factor 2 - pharmacology; Fibrosis; Heart - physiology; Heart Failure - physiopathology; Humans; Immunohistochemistry; Male; Microscopy, Confocal; Myocardium - metabolism; Myofibroblasts - metabolism; Tissue Inhibitor of Metalloproteinases - metabolism; Transforming Growth Factor beta1 - metabolism
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-015-0510-4

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.