Transplanted microvessels improve pluripotent stem cell–derived cardiomyocyte engraftment and cardiac function after infarction in rats

Abstract

Human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) offer an unprecedented opportunity to remuscularize infarcted human hearts. However, studies have shown that most hiPSC-CMs do not survive after transplantation into the ischemic myocardial environment, limiting their regenerative potential and clinical application. We established a method to improve hiPSC-CM survival by cotransplanting ready-made microvessels obtained from adipose tissue. Ready-made microvessels promoted a sixfold increase in hiPSC-CM survival and superior functional recovery when compared to hiPSC-CMs transplanted alone or cotransplanted with a suspension of dissociated endothelial cells in infarcted rat hearts. Microvessels showed unprecedented persistence and integration at both early (~80%, week 1) and late (~60%, week 4) time points, resulting in increased vessel density and graft perfusion, and improved hiPSC-CM maturation. These findings provide an approach to cell-based therapies for myocardial infarction, whereby incorporation of ready-made microvessels can improve functional outcomes in cell replacement therapies.

Human Engineered Heart Tissue Patches Remuscularize the Injured Heart in a Dose-Dependent Manner

“…There is growing evidence that cardiomyocyte proliferation participates in graft development after transplantation of pluripotent stem cell–derived cardiomyocytes. 39 , 41 , 42 Yet, a comprehensive analysis was still lacking. We therefore systematically analyzed cardiomyocyte cell cycle activity.…”

Pro-regenerative Extracellular Matrix Hydrogel Prevents and Mitigates Pathological Alterations of Pelvic Muscles Following Birth Injury

“…Data that followed a parametric distribution were compared using a Student's t-test, or a one-way analysis of variance followed by Tukey's post hoc pairwise comparisons. Non-parametrically distributed variables, such as fiber area, were analyzed by Mann-Whitney or Kruskal-Wallis test followed by Dunn's pairwise comparisons (48,49). Data were analyzed using GraphPad Prism v8.0, San Diego, CA.…”

Engineered Human Cardiac Microtissues: The State-of-the-(He)art

“…25 In a regenerative medicine setting, improved engraftment of hiPSC-CMs into ischemic rat hearts by co-transplantation with microvessels has led to significant improvement in hiPSC-CM maturation. 26 In line with the relevance of ECs in CM maturation and function described in vivo, recent in vitro studies have been aimed at creating more complex cardiac microtissues by incorporating ECs. One study determined that including ECs into small, cardiac spheroids resulted in upregulation of ion channel and calcium handling genes, which indicates improved maturity.…”

“…Moreover, the crosstalk between CMs and ECs is an important process for normal heart development and function, coordinating angiogenesis with CM hypertrophy during heart development 25 . In a regenerative medicine setting, improved engraftment of hiPSC‐CMs into ischemic rat hearts by co‐transplantation with microvessels has led to significant improvement in hiPSC‐CM maturation 26 …”