Abstract P1142: Engineering Vascular Therapies With Angiogenic Factors For Cardiac Regeneration And Tissue Remodeling

Abstract

The limited regenerative capacity of the adult human heart presents a critical need to stabilize and support injured heart muscle to mitigate the progression of heart failure. The effectiveness of remuscularization therapies using human induced pluripotent stem cell derived cardiomyocytes depends host mediated angiogenesis to direct the formation of stable, perfused vascular networks within the engineered cardiac implant. We hypothesize that potent combinations of growth factors will stimulate angiogenesis in the myocardium and increase vascular development in engineered cardiac tissue. In a fractional factorial experiment, we assessed the effect of ten growth factors, cytokines and enzymes: VEGF, bFGF, Shh, PDGF, IGF-1, EGF, TGF-β1, Ang-1, MCP-1 and MMP-9 on in vivo angiogenesis in a subcutaneous Matrigel plug assay in the rat. Five factors were highly potent by metrics of vessel density and vascular cell recruitment in explants and warranted further investigation. We then designed a two-level, fractional factorial experiment using a defined collagen-alginate gel to deliver high/low doses of these 5 factors subcutaneously to elucidate main effects and two-way interactions that regulate vessel development in vivo . After 7 days, Griffonia Simplicfolia lectin I was administered to label perfused vasculature then explants were removed and processed for immunohistochemistry. Our data show that 3 unique cocktails yielded a 10-fold increase in lumen density, a 3.3-fold increase in lumen size, and a 3.7-fold increase in endothelial cell recruitment relative to unloaded controls. Ongoing analyses will determine which angiogenic cocktail to deliver in a customizable biomaterial-based vascular therapy for applications in the heart. This novel therapy will be delivered with an engineered cardiac tissue onto the epicardium in a rat I/R MI model to quantify vascular remodeling in the implant and underlying host tissue and whole heart function over 4 weeks. In conclusion, we have identified five potent angiogenic factors for modulating revascularization responses and our ongoing work aims to understand the potential synergy between revascularization and remuscularization therapies for heart regeneration.