Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease.
OBJECTIVE
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.
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.
Kuei-Chuan
KC
Lee
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.
Han-Chieh
HC
Lin
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.
Yi-Hsiang
YH
Huang
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.
Shih-Chieh
SC
Hung
D064591:Allografts; D000818:Animals; D017209:Apoptosis; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003208:Concanavalin A / Q000633:toxicity; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D007371:Interferon-gamma / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010641:Phenotype; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
C556062:IL10 protein, mouse; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D003208:Concanavalin A; D016753:Interleukin-10; D007371:Interferon-gamma
Concanavalin A hepatitis; Interleukin 1 receptor antagonist; Interleukin 10; Macrophages; Mesenchymal stem cells