Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells.
Fulminant hepatic failure (FHF) is a clinical syndrome characterized by sudden and severe impairment of liver function. Mesenchymal stem cells (MSCs) have been proposed as a promising therapeutic approach for FHF. In this study we used Propionibacterium acnes (P. acnes)-primed, lipopolysaccharide (LPS)-induced liver injury in mice as an animal model of human FHF. We demonstrated that administration of MSCs significantly ameliorated liver injury and improved the survival rates of mice subjected to P. acnes plus LPS-induced FHF. Allogeneic MSCs showed similar treatment efficacy as autologous MSCs did in FHF. Treatment efficacy of MSCs could be attributed to decreased infiltration and activation of CD4(+) T cells in the liver, inhibition of T helper 1 cells, and induction of regulatory T cells (Tregs). Moreover, decreased DNA copies of P. acnes were detected in the liver of MSC-treated mice. Intriguingly, a distinct liver population of CD11c(+) MHCII(hi) CD80(lo) CD86(lo) regulatory dendritic cells (DCs) was induced by MSCs. Moreover, these DCs induced Treg differentiation through transforming growth factor-β production. Further mechanistic studies demonstrated that MSC-derived prostaglandin E2 and one of its receptors, EP4, played essential roles in the differentiation of CD11c(+) B220(-) DC precursors into regulatory DCs in a phosphoinositide 3-kinase-dependent manner.


CONCLUSIONS
MSCs induce regulatory DCs from CD11c(+) B220(-) DC precursors. This study elucidates an immunoregulatory mechanism of MSCs and lays a foundation for application of MSCs in FHF therapy.
Shanghai Institute of Immunology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM, Shanghai, China.
Yi
Y
Zhang
Wei
W
Cai
Qingrong
Q
Huang
Yuting
Y
Gu
Yufang
Y
Shi
Jiefang
J
Huang
Fang
F
Zhao
Qiang
Q
Liu
Xunbin
X
Wei
Min
M
Jin
Changping
C
Wu
Qing
Q
Xie
Yi
Y
Zhang
Bing
B
Wan
Yanyun
Y
Zhang
D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D016908:Gram-Positive Bacterial Infections / Q000150:complications*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000382:microbiology* / Q000628:therapy*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011425:Propionibacterium acnes; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D008070:Lipopolysaccharides; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D016212:Transforming Growth Factor beta