Transplanting human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) tissue sheets effectively treat ischemic cardiomyopathy. Cardiac functional recovery relies on graft survival in which angiogenesis played an important part. ONO-1301 is a synthetic prostacyclin analog with proangiogenic effects. We hypothesized that transplantation of hiPSC-CM tissue sheets with slow-release ONO-1301 scaffold could promote hostgraft angiogenesis, enhance tissue survival and therapeutic effect.
We developed hiPSC-CM tissue sheets with ONO-1301 slow-release scaffold and evaluated their morphology, gene expression, and effects on angiogenesis. Three tissue sheet layers were transplanted into a rat myocardial infarction (MI) model. Left ventricular ejection fraction, gene expression in the MI border zone, and angiogenesis effects were investigated 4 weeks after transplantation.
In vitro assessment confirmed the slow-release of ONO-1301, and its pro-angiogenesis effects. In addition, in vivo data demonstrated that ONO-1301 administration positively correlated with graft survival. Cardiac tissue as thick as ∼900 μm was retained in the ONO (+) treated group. Additionally, left ventricular ejection fraction of the ONO (+) group was significantly enhanced, compared to ONO (−) group. The ONO (+) group also showed significantly improved interstitial fibrosis, higher capillary density, increased number of mature blood vessels, along with an enhanced supply of oxygen, and nutrients.
Slow-release ONO-1301 scaffold provided an efficient delivery method for thick hiPSC-CM tissue. ONO-1301 promotes angiogenesis between the host and graft and improves nutritional and oxygen supply, thereby enhancing the survival of transplanted cells, effectively improving ejection fraction, and therapeutic effects.
Abbreviations:cTnT (cardiac muscle troponin T), FS (fractional shortening), FPKM (fragments per kilobase of exon per million mapped fragments), hiPSCs (human induced pluripotent stem cells), hiPSC-CMs (human induced pluripotent stem cell-derived cardiomyocytes), HCF (human cardiac fibroblasts), HE staining (hematoxylin and eosin staining), HGF (hepatocyte growth factor), HIF-1α (hypoxia-induced factor-1 alpha (HIF1A)), HUVECs (human umbilical vein endothelial cells), HNA (human nuclear antigen), IL-6 (interleukin 6), LVEF (left ventricular ejection fraction), MI (myocardial infarction), ONO-1301SR (slow-release ONO-1301), PLGA (poly(lactic-co-glycolic acid)), PGI2 (prostacyclin or prostaglandin I2), RT-PCR (reverse transcriptase-polymerase chain reaction), SDF-1 (stromal cell-derived factor-1), TGF-β1 (transforming growth factor beta 1), TXA2 (thromboxane A2), VEGF (vascular endothelial growth factor)
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Published online: February 09, 2023
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