Human endoderm stem cells reverse inflammation-related 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 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.

Type 2 Cystatins and Their Roles in the Regulation of Human Immune Response and Cancer Progression

“…CYS1 can directly bind to IFNGR1/2, acting as a competitive inhibitor of the pro-inflammatory cytokine IFN-γ. As a consequence, CYS1 inhibits the activation of the JAK/STAT1 pathway induced by IFN-γ and promotes the M2 polarization of macrophages in the liver [94]. In summary, CYS1 plays a role in the allergic Th2 immune response and anti-inflammatory processes.…”

“…CCL18 is an M2 macrophage polarizing cytokine that induces immunosuppression and antiinflammatory responses [92,93]. In addition, CST1 plays an important role in introducing an anti-inflammatory response in acute liver failure (ALF) models [94]. CYS1 can directly bind to IFNGR1/2, acting as a competitive inhibitor of the pro-inflammatory cytokine IFN-γ.…”

Nanozymes with Broad-Spectrum Scavenging of Reactive Oxygen Species (ROS) Alleviate Inflammation in Acute Liver Injury

“…6 It is generally known that inflammatory reaction plays a crucial role in liver repair and recover from damage. 7 Persistent inflammation caused by oxidative stress impedes liver repair and promotes secondary hepatocyte injury. 8 Liver pathologies often exhibit Kupffer cells (liver resident macrophages) infiltration, increased pro-inflammatory mediator, and hepatic steatosis.…”

“…Inflammation is an adaptive response for pathogen clearance and tissue repair . It is generally known that inflammatory reaction plays a crucial role in liver repair and recover from damage . Persistent inflammation caused by oxidative stress impedes liver repair and promotes secondary hepatocyte injury .…”

Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes

“…Acute liver failure (ALF) is a complication of drug toxicity, infection, or destructive immune responses [ 11 ]. The liver can be pathologically damaged by the activation of its innate immune function, even in the absence of infection.…”