Abstract 18510: A Technology for Cardiac Regeneration Using Human iPS Cell-Derived Cardiac Tissue Including Multiple Cardiovascular Lineages
Introduction: To realize cardiac regeneration using human induced pluripotent stem cells (hiPSCs), efficient differentiation from hiPSCs to defined cardiovascular populations (cardiomyocytes [CMs]/ endothelial cells [ECs]/ vascular mural cells [MCs]), and a format for fair engraftment are required. We previously reported that transplantation of hiPSC-derived cardiac tissue sheet (CTS) including CMs, ECs and MCs to a rat myocardial infarction (MI) model ameliorated cardiac dysfunction and regenerated human myocardium onto a rat heart (Sci Rep 2014). We have also reported a technology of multiple layering of cell sheets avoiding central necrosis during in vitro culture using gelatin hydrogel microspheres (GHMs) (Sci Rep 2015). Here we integrated these technologies to generate 15-layered Human iPSC-derived Cardiac Tissue (HiCT-15) and validated the enhanced efficacy of functional recovery and myocardial regeneration. METHODS &
Results: We applied a high-density monolayer culture method which induce vascular cells (ECs/MCs) together with CMs (Sci Rep 2014). These cells were transferred onto temperature-responsive culture dishes (UpCell; CellSeed, Tokyo, Japan) to form hiPSC-CTSs. We generated 3-dimensional HiCT-15s with approximately 0.7 mm thickness by stacking 15 CTSs with insertion of GHMs between each CTS to overcome the stacking limitation of hypoxia. The HiCT-15 was transplanted onto a MI athymic rat heart one-week after MI. Echocardiogram showed significantly higher functional recovery after HiCT-15 transplantation compared to that in rats receiving 15-layered CTSs without GHM (control) or in sham-operated rats (fractional shortening 12 weeks after surgery: sham vs control vs HiCT-15, 24±3.3 vs 40±3.8 vs 56±3.5%, P<0.01), reaching to comparable level as those before MI induction (55±3%). Immunostaining 4 weeks after implantation showed significantly higher engraftment of human cells as a regenerated myocardium compared to that in control. The regenerated myocardium was vascularized by host-derived vasculature confirmed by lectin perfusion analysis.
Conclutions: Transplantation of HiCT would be a valuable technological basis for hiPSC-based cardiac regenerative therapy.
Author Disclosures: H. Masumoto: None. K. Yamamizu: None. T. Ikuno: None. H. Takakubo: None. K. Minakata: None. T. Ikeda: None. Y. Tabata: None. J. Yamashita: Research Grant; Significant; Nippon Boehringer Ingelheim Co.. Other Research Support; Modest; Takara Bio Inc.. Ownership Interest; Modest; iHeart Japan Co..
- © 2016 by American Heart Association, Inc.