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.

人类胚胎干细胞（hESCs）可以无限地自我更新并在体外分化为肝细胞，包括可膨胀的肝母细胞（HBs）和类肝细胞（HLCs）。因此，hESC衍生的HBs可能成为严重肝损害的细胞疗法的可再生细胞来源。但是，这种细胞疗法的主要挑战之一是源自hESC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，可以通过异位表达免疫抑制分子CTLA4-Ig和PD-L1（称为CP HBs）来保护hESC衍生的HBs免受同种异体免疫排斥。像从正常hESC衍生的HBs一样，CP HBs能够修复动物模型中的肝损伤。使用重组有人类免疫系统的人源化小鼠（Hu-小鼠），我们显示CP HBs受到同种异体免疫系统的保护，可以在Hu-小鼠中长期存活。这些数据支持将CP HBs发展为治疗严重肝损伤的细胞疗法的可行性。