Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells
- 234 Downloads
Sepsis is a leading cause of death in intensive care units that can result in acute hepatic damage. Animal experiments and clinical trials have shown that mesenchymal stem cell (MSC) therapy has some beneficial in several liver diseases. However, the protective effects of MSC therapy on sepsis-induced hepatic damage and associated mechanisms are not completely understood. The aim of the present study was to investigate the effects of MSCs on sepsis-induced liver injury and underlying mechanisms. A rat model of sepsis-induced liver injury was established by cecal ligation and puncture, and serum alanine aminotransferase and aspartate transaminase activities as well as liver histological changes were measured. Inflammatory cytokines, Kupffer cell M1 phenotype markers, and associated signal molecules were also determined in septic rats and in lipopolysaccharide (LPS)-treated Kupffer cells. Our results showed that injection of MSCs attenuated sepsis-induced liver injury. Treatment with MSCs inhibited activation of Kupffer cells towards M1 phenotype, attenuated TNF-α and IL-6 expression, and promoted IL-4 and IL-10 expression in septic rats and LPS-treated Kupffer cells. Furthermore, MSCs also inhibited the nuclear translocation of nuclear factor-kappa B in LPS-challenged Kupffer cells and the liver of septic rats. These results indicated that MSCs attenuated sepsis-induced liver injury through suppressing M1 polarization of Kupffer cells.
KeywordsSepsis Mesenchymal stem cells Kupffer cells Liver injury
This study was supported by Science and Technology Planning Project of Guangdong Province, China (Grant number 32415102) and Jinan University’s Scientific Research Cultivation and Innovation Fund (Grant number 11615481).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Research involving human and/or animal rights
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the guide for the care and use of laboratory animals at Jinan University School of Medicine.
- 5.Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21(1):240–252Google Scholar
- 9.Drommelschmidt K, Serdar M, Bendix I, Herz J, Bertling F, Prager S, Keller M, Ludwig AK, Duhan V, Radtke S, de Miroschedji K, Horn PA, van de Looij Y, Giebel B, Felderhoff-Muser U (2017) Mesenchymal stem cell-derived extracellular vesicles ameliorate inflammation-induced preterm brain injury. Brain Behav Immun 60:220–232CrossRefGoogle Scholar
- 13.Suk KT, Yoon JH, Kim MY, Kim CW, Kim JK, Park H, Hwang SG, Kim DJ, Lee BS, Lee SH, Kim HS, Jang JY, Lee CH, Kim BS, Jang YO, Cho MY, Jung ES, Kim YM, Bae SH, Baik SK (2016) Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial. Hepatology 64(6):2185–2197CrossRefGoogle Scholar
- 15.Lin BL, Chen JF, Qiu WH, Wang KW, Xie DY, Chen XY, Liu QL, Peng L, Li JG, Mei YY, Weng WZ, Peng YW, Cao HJ, Xie JQ, Xie SB, Xiang AP, Gao ZL (2017) Allogeneic bone marrow-derived mesenchymal stromal cells for hepatitis B virus-related acute-on-chronic liver failure: a randomized controlled trial. Hepatology 66(1):209–219CrossRefGoogle Scholar
- 19.Németh K, Leelahavanichkul A, Yuen PS, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey E (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15(1):42–49CrossRefGoogle Scholar
- 25.Chao YH, Wu HP, Wu KH, Tsai YG, Peng CT, Lin KC, Chao WR, Lee MS, Fu YC (2014) An increase in CD3 + CD4 + CD25 + regulatory T cells after administration of umbilical cord-derived mesenchymal stem cells during sepsis. PLoS ONE 9(10):e110338. https://doi.org/10.1371/journal.pone.0110338 CrossRefGoogle Scholar
- 28.Wan J, Benkdane M, Teixeira-Clerc F, Bonnafous S, Louvet A, Lafdil F, Pecker F, Tran A, Gual P, Mallat A, Lotersztajn S, Pavoine C (2014) M2 Kupffer cells promote M1 Kupffer cell apoptosis: a protective mechanism against alcoholic and nonalcoholic fatty liver disease. Hepatology 59(1):130–142CrossRefGoogle Scholar
- 29.Maggini J, Mirkin G, Bognanni I, Holmberg J, Piazzón IM, Nepomnaschy I, Costa H, Cañones C, Raiden S, Vermeulen M, Geffner JR (2010) Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS ONE 5(2):e9252. https://doi.org/10.1371/journal.pone.0009252 CrossRefGoogle Scholar