利用免疫逃避的人胚胎干细胞衍生肝祖细胞修复急性肝损伤

Repair of acute liver damage with immune evasive hESC derived hepato-blasts.

作者信息

Liu Jingfeng, Pan Tingcai, Chen Yan, Liu Ying, Yang Fan, Chen Qu, Abbas Nasir, Zhong Mingyan, Zhang Qianbing, Xu Yang, Li Yin-Xiong

机构信息

Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.

Institute of Public Health, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou 510530, China; University of Chinese Academy of Science, Beijing 100049, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.

出版信息

Stem Cell Res. 2020 Dec;49:102010. doi: 10.1016/j.scr.2020.102010. Epub 2020 Sep 26.

DOI:10.1016/j.scr.2020.102010

PMID:33011360

Abstract

Human embryonic stem cells (hESCs) can undergo unlimited self-renewal and differentiate into hepatic cells, including expandable hepato-blasts (HBs) and hepatocyte-like cells (HLCs) in vitro. Therefore, hESC-derived HBs have the potential to become a renewable cell source for cell therapy of serious liver damage. However, one of the key challenges for such cell therapy is the allogeneic immune rejection of hESC-derived HBs. To overcome this challenge, we developed a strategy to protect the hESC-derived HBs from allogeneic immune rejection by ectopically expressing immune suppressive molecules CTLA4-Ig and PD-L1, denoted CP HBs. Like HBs derived from normal hESCs, CP HBs are capable of repairing liver damage in animal models. Using humanized mice (Hu-mice) reconstituted with human immune system, we showed that CP HBs are protected from allogeneic immune system and can survive long-term in Hu-mice. These data support the feasibility to develop CP HBs into a cell therapy to treat serious liver damage.

摘要

人类胚胎干细胞（hESCs）能够进行无限自我更新，并在体外分化为肝细胞，包括可扩增的肝祖细胞（HBs）和肝样细胞（HLCs）。因此，hESC来源的HBs有潜力成为严重肝损伤细胞治疗的可再生细胞来源。然而，这种细胞治疗的关键挑战之一是hESC来源的HBs的同种异体免疫排斥。为了克服这一挑战，我们开发了一种策略，通过异位表达免疫抑制分子CTLA4-Ig和PD-L1来保护hESC来源的HBs免受同种异体免疫排斥，称为CP HBs。与源自正常hESCs的HBs一样，CP HBs能够在动物模型中修复肝损伤。利用用人免疫系统重建的人源化小鼠（Hu-小鼠），我们表明CP HBs受到同种异体免疫系统的保护，并且能够在Hu-小鼠中长期存活。这些数据支持了将CP HBs开发成治疗严重肝损伤的细胞疗法的可行性。