Human Endoderm Stem Cells Reverse Acute Liver Failure Through Cystatin SN-Mediated Inhibition of Interferon Signaling

Abstract

Acute liver failure (ALF) is a life-threatening disease that occurs secondary to drug toxicity, infection or a devastating immune response. Orthotopic liver transplantation and hepatocyte transplantation are effective treatments but are limited due to 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. Human endoderm stem cells (hEnSCs) are germ layer-specific, self-renewable and nontumorigenic cells derived from pluripotent stem cells. Here, we report that hEnSCs transplanted into the liver are able to effectively reverse hepatic injury in rodent and swine ALF models. We demonstrate that hEnSCs tune the local immune microenvironment by skewing macrophages/Kupffer cells towards an anti-inflammatory state and by reducing 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 activation state, 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. hEnSC transplantation represents a novel and powerful cell therapeutic treatment for ALF.