Kuei-Chuan Lee1, Han-Chieh Lin2, Yi-Hsiang Huang3, Shih-Chieh Hung4. 1. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 2. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan. 3. Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Infection and Immunity Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan. Electronic address: yhhuang@vghtpe.gov.tw. 4. Stem Cell Laboratory, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan; Integrative Stem Cell Center, Chinese Medical University, Taichung, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. Electronic address: hungsc@vghtpe.gov.tw.
Abstract
BACKGROUND & AIMS: Autologous transplantation of mesenchymal stem cells (MSCs) reduces concanavalin A (Con A)-induced hepatic injury in mice. However, the mechanism is unclear and the therapeutic effect of allo-transplantation remains unknown. Our aim was to investigate the effects and mechanisms related to allo-transplantation of MSCs when used to treat Con A hepatic injury. METHODS: After Con A-induced liver injury was created in C57BL/6J mice, MSCs derived from BALB/c mice or a vehicle control was administered. RESULTS: Allo-transplantation of MSCs derived from BALB/c mice attenuated hepatic apoptosis in C57BL/6J mice that had undergone Con A-induced liver injury. MSCs increased the level of serum interleukin (IL)-10 and the phosphorylation of hepatic STAT3, but decreased the level of hepatic IFN-γ and phospho-STAT1. Notably, the administered MSCs were trapped mostly in the lungs and promoted the macrophage M2 switch, which contributed to the increased IL10 levels in the lungs and serum. Loss of the therapeutic effect was observed after knock-down of the expression of interleukin 1 receptor antagonist (IL1Ra) in the MSCs. In vitro investigation supported the hypothesis that MSCs are able to switch Con A-stimulated macrophages to the M2 phenotype, which results in an increase in IL10 production. CONCLUSIONS: Allo-transplantation of MSCs reduces Con A liver injury by increasing IL10 production through an IL1Ra dependent macrophage switch.
BACKGROUND & AIMS: Autologous transplantation of mesenchymal stem cells (MSCs) reduces concanavalin A (Con A)-induced hepatic injury in mice. However, the mechanism is unclear and the therapeutic effect of allo-transplantation remains unknown. Our aim was to investigate the effects and mechanisms related to allo-transplantation of MSCs when used to treat Con A hepatic injury. METHODS: After Con A-induced liver injury was created in C57BL/6J mice, MSCs derived from BALB/c mice or a vehicle control was administered. RESULTS: Allo-transplantation of MSCs derived from BALB/c mice attenuated hepatic apoptosis in C57BL/6J mice that had undergone Con A-induced liver injury. MSCs increased the level of serum interleukin (IL)-10 and the phosphorylation of hepatic STAT3, but decreased the level of hepatic IFN-γ and phospho-STAT1. Notably, the administered MSCs were trapped mostly in the lungs and promoted the macrophage M2 switch, which contributed to the increased IL10 levels in the lungs and serum. Loss of the therapeutic effect was observed after knock-down of the expression of interleukin 1 receptor antagonist (IL1Ra) in the MSCs. In vitro investigation supported the hypothesis that MSCs are able to switch Con A-stimulated macrophages to the M2 phenotype, which results in an increase in IL10 production. CONCLUSIONS: Allo-transplantation of MSCs reduces Con A liver injury by increasing IL10 production through an IL1Ra dependent macrophage switch.