Human iPSC cardiomyocyte patch transplantation modifies extracellular matrix and fibroblast behavior after myocardial infarction

Myocardial infarction (MI) followed by chronic heart failure is the main cause of mortality of heart diseases. Although reparative cell transplantation therapies with pluripotent stem cell-derived cardiomyocytes (CMs) represent a promising therapeutic strategy, molecular mechanisms of the therapy remain elusive. Here, we show that transplantation of the hiPSC-derived CM patch onto the damaged heart after MI, increases the ratio of collagen type I against collagen type III to modulate alignment of the collagen fibers at the infarcted zone. As a result, tissue elasticity of the heart is improved and fibrosis at the remote zone is reduced. Mechanistically, we find that hiPSC-derived CM patches secrete TGF-ß1, directly inducing collagen type I production in fibroblasts but not collagen type III. Our results suggest the direct effect of the transplanted CM patch on the cardiac fibroblasts to improve elasticity of the damaged heart, resulting in functional recovery after MI. Overall design: Bulk RNA-seq profiling of rat left ventricular tissues (ischemic lesion, border zone, and uninjured remote myocardium) in a myocardial infarction model. One week after LAD ligation, human iPSC-derived cardiomyocyte patches were transplanted onto the ischemic area of the left ventricle. Hearts were collected at Day 3, 1 week, and 4 weeks after transplantation. To avoid cross-species contamination, reads were aligned to a combined rat (Rnor_6.0) and human (GRCh38) reference, and only rat-derived uniquely mapped reads were retained and reported in this dataset.