The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.
Original Pre-Clinical Science|Articles in Press

ONO-1301 enhances post-transplantation survival of human induced pluripotent stem cell-derived cardiac tissue sheet by promoting angiogenesis

Published:February 09, 2023DOI:


      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.



      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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