诱导多能干细胞
清脆的
Cas9
类有机物
基因组编辑
表型
人诱导多能干细胞
移植
人口
生物
遗传增强
胚胎干细胞
细胞生物学
癌症研究
基因
医学
遗传学
内科学
环境卫生
作者
Jeong Sang Son,Chul‐Yong Park,Gyunggyu Lee,Ji Young Park,Hyo Jin Kim,Gyeongmin Kim,Kyun Yoo,Dong-Hun Woo,Choongseong Han,Sang Kyum Kim,Han-Jin Park,Dong Wook Kim,Jong Hoon Kim
出处
期刊:Biomaterials
[Elsevier]
日期:2022-04-01
卷期号:283: 121429-121429
被引量:16
标识
DOI:10.1016/j.biomaterials.2022.121429
摘要
The bleeding disorder hemophilia A (HA) is caused by a single-gene (F8) defect and its clinical symptom can be substantially improved by a small increase in the plasma coagulation factor VIII (FVIII) level. In this study, we used F8-defective human induced pluripotent stem cells from an HA patient (F8d-HA hiPSCs) and F8-corrected (F8c) HA hiPSCs produced by CRISPR/Cas9 genome engineering of F8d-HA hiPSCs. We obtained a highly enriched population of CD157+ cells from CRISPR/Cas9-edited F8c-HA hiPSCs. These cells exhibited multiple cellular and functional phenotypes of endothelial cells (ECs) with significant levels of FVIII activity, which was not observed in F8d-HA hiPSC-ECs. After transplantation, the engineered F8c-HA hiPSC-ECs dramatically changed bleeding episodes in HA animals and restored plasma FVIII activity. Notably, grafting a high dose of ECs substantially reduced the bleeding time during multiple consecutive bleeding challenges in HA mice, demonstrating a robust hemostatic effect (90% survival). Furthermore, the engrafted ECs survived more than 3 months in HA mice and reversed bleeding phenotypes against lethal wounding challenges. We also produced F8c-HA hiPSC-derived 3D liver organoids by assembling three different cell types in microwell devices and confirmed its therapeutic effect in HA animals. Our data demonstrate that the combination of genome-engineering and iPSC technologies represents a novel modality that allows autologous cell-mediated gene therapy for treating HA.
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