ONO-1301 enhances post-transplantation survival of human induced pluripotent stem cell-derived cardiac tissue sheet by promoting angiogenesis
ONO-1301 enhances post-transplantation survival of human induced pluripotent stem cell-derived cardiac tissue sheet by promoting angiogenesis
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DOI：
10.1016/j.healun.2023.01.018
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发表时间：
2023-05-15
影响因子：
8.9
通讯作者：
Miyagawa, Shigeru
中科院分区：
文献类型：
--
作者：
Qu, Xiang;Li, Junjun;Miyagawa, Shigeru
背景技术背景：移植人诱导多能干细胞衍生的心肌细胞（hiPSC-CM）组织片有效治疗缺血性心肌病。心脏功能的恢复依赖于移植物的存活，其中血管生成起着重要作用。ONO-1301是一种具有促血管生成作用的合成前列环素类似物。方法：采用ONO-1301缓释支架构建hiPSC-CM组织片，观察其形态学、基因表达及对血管生成的影响。将三层组织片移植到大鼠心肌梗死（MI）模型中。左心室射血分数，心肌梗死边缘区的基因表达，和血管生成的影响进行了调查4周后transplantation.RESULTS：在体外评估证实了ONO-1301的缓释，其促血管生成的作用。此外，体内数据表明ONO-1301给药与移植物存活正相关。ONO（+）处理组的心肌组织厚度可达>> 900 mm。ONO（+）组左室射血分数明显高于ONO（-）组。ONO（+）组还显示出显著改善的间质纤维化、更高的毛细血管密度、增加的成熟血管数量、沿着增强的氧气和营养物供应。ONO-1301促进宿主和移植物之间的血管生成，改善营养和氧气供应，从而提高移植细胞的存活率，有效提高射血分数和治疗效果。J Heart Lung Transplant 2023;42：716-729（c）2023 International Society for Heart and Lung Transplantation。All rights reserved.
BACKGROUND: 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.METHODS: We developed hiPSC-CM tissue sheets with ONO-1301 slow-release scaffold and eval-uated 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.RESULTS: 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 mm was retained in the ONO (+) treated group. Additionally, left ventricular ejection fraction of the ONO (+) group was significantly enhanced, com-pared 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.CONCLUSIONS: 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 improv-ing ejection fraction, and therapeutic effects.J Heart Lung Transplant 2023;42:716-729 (c) 2023 International Society for Heart and Lung Transplantation. All rights reserved.