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

• Published in: The Journal of heart and lung transplantation Vol. 42; no. 6; pp. 716 - 729
• Main Authors: Qu, Xiang, Li, Junjun, Liu, Li, Zhang, Jingbo, Hua, Ying, Suzuki, Kota, Harada, Akima, Ishida, Masako, Yoshida, Noriko, Okuzaki, Daisuke, Sakai, Yoshiki, Sawa, Yoshiki, Miyagawa, Shigeru
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2023
• Subjects: angiogenesis; Angiogenesis Inducing Agents - pharmacology; Animals; cardiac function; cardiomyocytes; Disease Models, Animal; hiPSCs; Humans; Induced Pluripotent Stem Cells - transplantation; Myocardial Infarction - therapy; Myocytes, Cardiac - metabolism; ONO-1301; Rats; Stroke Volume; Ventricular Function, Left; ONO-1301; LVEF; SDF-1; HIF-1α; FS; FPKM; cardiomyocytes; RT-PCR; cTnT; cardiac function; MI; ONO-1301SR; PGI2; angiogenesis; HE staining; HGF; VEGF; HCF; IL-6; hiPSCs; TXA2; PLGA; hiPSC-CMs; TGF-β1; HNA; HUVECs
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2023.01.018

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.