高效扩增和 CRISPR-Cas9 介导的患者衍生肝细胞基因校正用于治疗遗传性肝病

IF 19.8 1区 医学 Q1 CELL & TISSUE ENGINEERING Cell stem cell Pub Date : 2024-05-20 DOI:10.1016/j.stem.2024.04.022
Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui
{"title":"高效扩增和 CRISPR-Cas9 介导的患者衍生肝细胞基因校正用于治疗遗传性肝病","authors":"Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui","doi":"10.1016/j.stem.2024.04.022","DOIUrl":null,"url":null,"abstract":"<p>Cell-based <em>ex vivo</em> gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines <em>ex vivo</em> large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.</p>","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":null,"pages":null},"PeriodicalIF":19.8000,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases\",\"authors\":\"Kun Zhang, Ping Wan, Liren Wang, Zhen Wang, Fangzhi Tan, Jie Li, Xiaolong Ma, Jin Cen, Xiang Yuan, Yang Liu, Zhen Sun, Xi Cheng, Yuanhua Liu, Xuhao Liu, Jiazhi Hu, Guisheng Zhong, Dali Li, Qiang Xia, Lijian Hui\",\"doi\":\"10.1016/j.stem.2024.04.022\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Cell-based <em>ex vivo</em> gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines <em>ex vivo</em> large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.</p>\",\"PeriodicalId\":9665,\"journal\":{\"name\":\"Cell stem cell\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":19.8000,\"publicationDate\":\"2024-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell stem cell\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.stem.2024.04.022\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL & TISSUE ENGINEERING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2024.04.022","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}
引用次数: 0

摘要

事实证明,在实体器官(尤其是肝脏)中进行基于细胞的体外基因治疗在技术上具有挑战性。在此,我们报告了肝细胞疗法临床应用的可行策略。我们首先通过大规模扩增患者肝细胞生成高质量的自体肝细胞。此外,增殖的患者来源肝细胞与通过筛选确定的 AAV2.7m8 变体一起,实现了 CRISPR-Cas9 介导的高效靶向整合,实现了对 FAH 或 OTC 中致病突变的功能性校正。重要的是,这些经过编辑的肝细胞能在损伤的小鼠肝脏中进行高水平的再填充和成熟,并在移植后成功治疗了酪氨酸血症小鼠。我们的研究结合了体外大规模细胞扩增和基因编辑患者来源的可移植肝细胞,这为治疗人类肝病提供了潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Efficient expansion and CRISPR-Cas9-mediated gene correction of patient-derived hepatocytes for treatment of inherited liver diseases

Cell-based ex vivo gene therapy in solid organs, especially the liver, has proven technically challenging. Here, we report a feasible strategy for the clinical application of hepatocyte therapy. We first generated high-quality autologous hepatocytes through the large-scale expansion of patient-derived hepatocytes. Moreover, the proliferating patient-derived hepatocytes, together with the AAV2.7m8 variant identified through screening, enabled CRISPR-Cas9-mediated targeted integration efficiently, achieving functional correction of pathogenic mutations in FAH or OTC. Importantly, these edited hepatocytes repopulated the injured mouse liver at high repopulation levels and underwent maturation, successfully treating mice with tyrosinemia following transplantation. Our study combines ex vivo large-scale cell expansion and gene editing in patient-derived transplantable hepatocytes, which holds potential for treating human liver diseases.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Cell stem cell
Cell stem cell 生物-细胞生物学
CiteScore
37.10
自引率
2.50%
发文量
151
审稿时长
42 days
期刊介绍: Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.
期刊最新文献
CRISPRi/a screens in human iPSC-cardiomyocytes identify glycolytic activation as a druggable target for doxorubicin-induced cardiotoxicity All roads lead to cholesterol: Modulating lipid biosynthesis in multiple sclerosis patient-derived models Trained immunity in the bone marrow: Hub of autoimmunity To BE or to PE: Prime editors provide more choices for epitope-editing-based immunotherapy Nurturing protectors: Macrophages in the human pancreatic islet
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1