Human embryonic stem cell-derived immunity-and-matrix regulatory cells promote intrahepatic cell renewal to rescue acute liver failure

Abstract

Acute liver failure (ALF) is a clinical syndrome characterized by the accelerated development of hepatocyte necrosis and significant mortality. Given that liver transplantation is now the only curative treatment available for ALF, there is an urgent need to explore innovative therapies. Mesenchymal stem cells (MSCs) have been applied in preclinical studies for ALF. It had been demonstrated that human embryonic stem cell-derived immunity-and-matrix regulatory cells (IMRCs) met the properties of MSCs and had been employed in a wide range of conditions. In this study, we conducted a preclinical evaluation of IMRCs in the treatment of ALF and investigated the mechanism involved. ALF was induced in C57BL/6 mice via intraperitoneal administration of 50% CCl₄ (6 mL/kg) mixed with corn oil, followed by intravenous injection of IMRCs (3 × 10⁶ cells/each). IMRCs improved histopathological changes in the liver and reduced alanine transaminase (ALT) or aspartate transaminase (AST) levels in serum. IMRCs also promoted cell renewal in the liver and protected it from CCl₄ damage. Furthermore, our data indicated that IMRCs protected against CCl₄-induced ALF by regulating the IGFBP2-mTOR-PTEN signaling pathway, which is associated with the repopulation of intrahepatic cells. Overall, IMRCs offered protection against CCl₄-induced ALF and were capable of preventing apoptosis and necrosis in hepatocytes, which provided a new perspective for treating and improving the prognosis of ALF.

Keywords: Acute liver failure; Cell therapy; Hepatocytes; Mesenchymal stem cells; Regenerative medicine.