These authors contributed equally to this work.
Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells
Article first published online: 20 DEC 2013
Copyright © 2013 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Volume 59, Issue 2, pages 671–682, February 2014
How to Cite
Zhang, Y., Cai, W., Huang, Q., Gu, Y., Shi, Y., Huang, J., Zhao, F., Liu, Q., Wei, X., Jin, M., Wu, C., Xie, Q., Zhang, Y., Wan, B. and Zhang, Y. (2014), Mesenchymal stem cells alleviate bacteria-induced liver injury in mice by inducing regulatory dendritic cells. Hepatology, 59: 671–682. doi: 10.1002/hep.26670
Potential conflict of interest: Nothing to report.
Supported by the Ministry of Science and Technology of China 2011CB966200 (to Y.Z.), Strategic Priority Research Program of the Chinese Academy of Sciences XDA01040000 (to Y.Z.), National Natural Science Foundation of China 81130057, 81071748 (to Y.Z.), the Program of Science and Technology Commission of Shanghai Municipality 11JC1411400, 11431920900 (to Y.Z.) and 11ZR1422400 (to W.C.), the Program of Chinese Academy of Science KSCX2-YW-R-245, KSCX2-YW-R-175 (to Y.Z.), and Leading Academic Discipline Project of Shanghai Municipal Education Commission J50207 (to Y.Z.).
- Issue published online: 29 JAN 2014
- Article first published online: 20 DEC 2013
- Accepted manuscript online: 8 AUG 2013 08:11AM EST
- Manuscript Accepted: 30 JUL 2013
- Manuscript Received: 23 JAN 2013
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+MHCIIhiCD80loCD86lo 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. Conclusion: 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. (Hepatology 2014;59:671–682)