急性肝衰竭（ALF）是由药物毒性、感染或致命的免疫反应导致的一种威胁生命的疾病。正位肝移植是一种有效的治疗方法，但由于供体器官短缺、需终身免疫抑制和手术挑战而受限。干细胞移植是一种有前途的替代疗法，因为干细胞具有免疫调节能力。我们报告，将来源于多能干细胞的特定胚层和无肿瘤的人类内胚层干细胞（hEnSCs）移植到肝脏中能够有效地改善多个啮齿动物和猪药物性ALF模型中的肝损伤。我们证实，hEnSCs通过将巨噬细胞/库普弗细胞朝着抗炎状态引向和减少浸润的单核/巨噬细胞和炎性T细胞来调节局部免疫微环境。从动物肝脏中分离的浸润和驻留的单核/巨噬细胞的单细胞转录组分析显示了显著的变化，包括与激活状态变化相一致的基因表达变化以及这些细胞之间动态的种群异质性。我们进一步证明，hEnSCs通过囊蛋白SN（CST1）介导的干扰素信号抑制调节巨噬细胞/库普弗细胞的激活状态，因此凸显CST1作为涉及过度激活干扰素的疾病的候选治疗药物。我们建议，hEnSC移植代表着一种新颖而强大的细胞治疗方法，可用于治疗ALF。©2023。作者。

Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation is an effective treatment but limited by the shortage of donor organs, the requirement for life-long immune suppression and surgical challenges. Stem cell transplantation is a promising alternative therapy for fulminant liver failure owing to the immunomodulatory abilities of stem cells. Here, we report that when transplanted into the liver, human endoderm stem cells (hEnSCs) that are germ layer-specific and nontumorigenic cells derived from pluripotent stem cells are able to effectively ameliorate hepatic injury in multiple rodent and swine drug-induced ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing the infiltrating monocytes/macrophages and inflammatory T helper cells. Single-cell transcriptomic analyses of infiltrating and resident monocytes/macrophages isolated from animal livers revealed dramatic changes, including changes in gene expression that correlated with the change of activation states, and dynamic population heterogeneity among these cells after hEnSC transplantation. We further demonstrate that hEnSCs modulate the activation state of macrophages/Kupffer cells via cystatin SN (CST1)-mediated inhibition of interferon signaling and therefore highlight CST1 as a candidate therapeutic agent for diseases that involve over-activation of interferons. We propose that hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.© 2023. The Author(s).