Abstract
Hypothesis and objective: We hypothesize that lowering heart stiffness improves heart regeneration induced by extracellular matrix (ECM) proteins. In this study we investigated heart post-injury responses in non-regenerative mice hearts with modulated tissue stiffness and ECM hydrogel. The objectives are 1) determining if heart stiffness affects heart regeneration in response to extracellular biomolecules; and 2) identifying specific signaling pathways that regulate fibroblasts and cardiomyocytes mechanosensitivity to extracellular proteins. Methods: P5 mouse heart stiffness was modulated by BAPN and genipin injections. Solubilized porcine fetal ECM was injected immediately after ligating coronary artery. Heart function and histology were conducted on day 3 and week 3 post-myocardial infarction (MI). A mice ventricle explant model was used to investigate the molecular mechanisms. Results: Heart stiffness was lowered from 50kPa to 9kPa by BAPN and increased to 142kPa by genipin. We observed that fetal ECM treatment preserved cardiac output, reduced fibrosis, and promoted cardiomyocyte cell cycle activity. Decreasing tissue stiffness further improved the therapeutic efficacy of fetal ECM on heart post-MI response (Fig.1). Decreasing tissue stiffness lowered fibrosis in non-ECM treated MI control hearts, but did not affect the other aspects. Using a ventricle explant model of various stiffness, molecular evidence demonstrated that agrin-YAP signaling pathway is involved in the mechano-regulation of fetal ECM-induced heart regeneration. Agrin expression was elevated and cardiomyocyte YAP activation was not affected by changing tissue stiffness in control (no-ECM) mechano-modulated explants. However, YAP activation in fetal-ECM treated explants was increased by softening tissue. We also demonstrated that ECM hydrogel inhibits fibroblast to myofibroblast differentiation through CAPG protein.
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