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利用TALENs对人诱导多能干细胞进行HLA DR基因组编辑可产生免疫耐受的树突状细胞。

HLA DR Genome Editing with TALENs in Human iPSCs Produced Immune-Tolerant Dendritic Cells.

作者信息

Kwon Yoo-Wook, Ahn Hyo-Suk, Lee Jin-Woo, Yang Han-Mo, Cho Hyun-Jai, Kim Seok Joong, Lee Shin-Hyae, Yang Heung-Mo, Jang Hyun-Duk, Kim Sung Joo, Kim Hyo-Soo

机构信息

Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.

Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.

出版信息

Stem Cells Int. 2021 May 20;2021:8873383. doi: 10.1155/2021/8873383. eCollection 2021.

Abstract

Although human induced pluripotent stem cells (iPSCs) can serve as a universal cell source for regenerative medicine, the use of iPSCs in clinical applications is limited by prohibitive costs and prolonged generation time. Moreover, allogeneic iPSC transplantation requires preclusion of mismatches between the donor and recipient human leukocyte antigen (HLA). We, therefore, generated universally compatible immune nonresponsive human iPSCs by gene editing. Transcription activator-like effector nucleases (TALENs) were designed for selective elimination of HLA DR expression. The engineered nucleases completely disrupted the expression of HLA DR on human dermal fibroblast cells (HDF) that did not express HLA DR even after stimulation with IFN-. Teratomas formed by HLA DR knockout iPSCs did not express HLA DR, and dendritic cells differentiated from HLA DR knockout iPSCs reduced CD4 T cell activation. These engineered iPSCs might provide a novel translational approach to treat multiple recipients from a limited number of cell donors.

摘要

尽管人类诱导多能干细胞(iPSC)可作为再生医学的通用细胞来源,但iPSC在临床应用中的使用受到高昂成本和较长生成时间的限制。此外,同种异体iPSC移植需要排除供体和受体人类白细胞抗原(HLA)之间的不匹配。因此,我们通过基因编辑生成了普遍兼容的免疫无反应性人类iPSC。设计转录激活样效应核酸酶(TALEN)以选择性消除HLA DR表达。工程核酸酶完全破坏了人皮肤成纤维细胞(HDF)上HLA DR的表达,即使在用IFN-刺激后,这些细胞也不表达HLA DR。由HLA DR敲除iPSC形成的畸胎瘤不表达HLA DR,并且从HLA DR敲除iPSC分化的树突状细胞减少了CD4 T细胞的活化。这些工程化的iPSC可能提供一种新的转化方法,从有限数量的细胞供体治疗多个受体。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b89b/8163544/a1300ce5b8a3/SCI2021-8873383.001.jpg

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