Skip to main content
SpringerLink
Log in

Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Nolan JP (2010) The role of intestinal endotoxin in liver injury: a long and evolving history. Hepatology 52(5):1829–1835

    Article  CAS  PubMed  Google Scholar 

  2. Kudo H, Takahara T, Yata Y, Kawai K, Zhang W, Sugiyama T (2009) Lipopolysaccharide triggered TNF-alpha-induced hepatocyte apoptosis in a murine non-alcoholic steatohepatitis model. J Hepatol 51(1):168–175

    Article  CAS  PubMed  Google Scholar 

  3. Kaffarnik MF, Lock JF, Vetter H, Ahmadi N, Lojewski C, Malinowski M, Neuhaus P, Stockmann M (2013) Early diagnosis of sepsis-related hepatic dysfunction and its prognostic impact on survival: a prospective study with the LiMAx test. Crit Care 17(5):R259

    Article  PubMed  PubMed Central  Google Scholar 

  4. Kobashi H, Toshimori J, Yamamoto K (2013) Sepsis-associated liver injury: Incidence, classification and the clinical significance. Hepatol Res 43(3):255–266

    Article  PubMed  Google Scholar 

  5. Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N (1995) Fulminant hepatic failure: summary of a workshop. Hepatology 21(1):240–252

    CAS  PubMed  Google Scholar 

  6. Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H (2000) The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag + T cells in T helper 1 immune responses. Immunol Rev 174:35–46

    Article  CAS  PubMed  Google Scholar 

  7. Thomson AW, Knolle PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10(11):753–766

    Article  CAS  PubMed  Google Scholar 

  8. Ashare A, Monick MM, Powers LS, Yarovinsky T, Hunninghake GW (2006) Severe bacteremia results in a loss of hepatic bacterial clearance. Am J Respir Crit Care Med 173(6):644–652

    Article  CAS  PubMed  PubMed Central  Google 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 60:220–232

    Article  CAS  PubMed  Google Scholar 

  10. Sargent A, Miller RH (2016) MSC Therapeutics in Chronic Inflammation. Curr Stem Cell Rep 2(2):168–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lai TS, Wang ZH, Cai SX (2015) Mesenchymal stem cell attenuates neutrophil-predominant inflammation and acute lung injury in an in vivo rat model of ventilator-induced lung injury. Chin Med J (Engl) 128(3):361–367

    Article  CAS  Google Scholar 

  12. Amin MA, Sabry D, Rashed LA, Aref WM, el-Ghobary MA, Farhan MS, Fouad HA, Youssef YA (2013) Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant 27(4):607–612

    Article  PubMed  Google 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):2185–2197

    Article  CAS  PubMed  Google Scholar 

  14. Wang L, Li J, Liu H, Li Y, Fu J, Sun Y, Xu R, Lin H, Wang S, Lv S, Chen L, Zou Z, Li B, Shi M, Zhang Z, Wang FS (2013) Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol 28(Suppl 1):85–92

    Article  CAS  PubMed  Google 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):209–219

    Article  CAS  PubMed  Google Scholar 

  16. Liang XJ, Chen XJ, Yang DH, Huang SM, Sun GD, Chen YP (2012) Differentiation of human umbilical cord mesenchymal stem cells into hepatocyte-like cells by hTERT gene transfection in vitro. Cell Biol Int 36(2):215–221

    Article  CAS  PubMed  Google Scholar 

  17. Rittirsch D, Huber-Lang MS, Flierl MA,Ward PA (2009) Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc 4(1):31–36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cusack CL, Swahari V, Hampton Henley W, Michael Ramsey J, Deshmukh M (2013) Distinct pathways mediate axon degeneration during apoptosis and axon-specific pruning. Nat Commun 4:1876

    Article  CAS  PubMed  Google 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):42–49

    Article  CAS  PubMed  Google Scholar 

  20. Horák J, Nalos L, Martínková V, Beneš J, Štengl M, Matějovič M (2017) Mesenchymal stem cells in sepsis and associated organ dysfunction: a promising future or blind alley? Stem Cells Int 2017:7304121. https://doi.org/10.1155/2017/7304121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mareschi K, Ferrero I, Rustichelli D, Aschero S, Gammaitoni L, Aglietta M, Madon E, Fagioli F (2006) Expansion of mesenchymal stem cells isolated from pediatric and adult donor bone marrow. J Cell Biochem 97(4):744–754

    Article  CAS  PubMed  Google Scholar 

  22. Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, Borlongan CV (2015) Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy 17(1):18–24

    Article  PubMed  Google Scholar 

  23. Wang HS, Hung SC, Peng ST, Huang CC, Wei HM, Guo YJ, Fu YS, Lai MC, Chen CC (2004) Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 22(7):1330–1337

    Article  PubMed  Google Scholar 

  24. Shin S, Kim Y, Jeong S, Hong S, Kim I, Lee W, Choi S (2013) The therapeutic effect of human adult stem cells derived from adipose tissue in endotoxemic rat model. Int J Med Sci 10(1):8–18

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Liu S, Yuan M, Hou K, Zhang L, Zheng X, Zhao B, Sui X, Xu W, Lu S, Guo Q (2012) Immune characterization of mesenchymal stem cells in human umbilical cord Wharton’s jelly and derived cartilage cells. Cell Immunol 278(1–2):35–44

    Article  CAS  PubMed  Google Scholar 

  27. Tacke F, Zimmermann HW (2014) Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 60(5):1090–1096

    Article  CAS  PubMed  Google 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):130–142

    Article  CAS  PubMed  Google 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang JW, Lee SM (2016) Resolvin D1 protects the liver from ischemia/reperfusion injury by enhancing M2 macrophage polarization and efferocytosis. Biochim Biophys Acta 1861(9Pt A):1025–1035. https://doi.org/10.1016/j.bbalip.2016.06.002

    Article  CAS  PubMed  Google Scholar 

  31. Xie J, Wu X, Zhou Q, Yang Y, Tian Y, Huang C, Meng X, Li J (2016) PICK1 confers anti-inflammatory effects in acute liver injury via suppressing M1 macrophage polarization. Biochimie 127:121–132

    Article  CAS  PubMed  Google Scholar 

  32. Courtine E, Pene F, Cagnard N, Toubiana J, Fitting C, Brocheton J, Rousseau C, Gerondakis S, Chiche JD, Ouaaz F, Mira JP (2011) Critical role of cRel subunit of NF-kB in sepsis survival. Infect Immun 79(5):1848–1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jin LY, Li CF, Zhu GF, Wu CT, Wang J, Yan SF (2014) Effect of siRNA against NF-kB on sepsis-induced acute lung injury in a mouse model. Mol Med Rep 10(2):631–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li H, Han W, Polosukhin V, Yull FE, Segal BH, Xie CM, Blackwell TS (2013) NF-kB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense. Mediators Inflamm 2013:503213. https://doi.org/10.1155/2013/503213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ha T, Xia Y, Liu X, Lu C, Liu L, Kelley J, Kalbfleisch J, Kao RL, Williams DL, Li C (2011) Glucan phosphate attenuates myocardial HMGB1 translocation in severe sepsis through inhibiting NF-kB activation. Am J Physiol Heart Circ Physiol 301(3):H848–H855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Fang JP, Liu Y, Li J, Liao WF, Hu YH, Ding K (2012) A novel small molecule, HK-156, inhibits lipopolysaccharide-induced activation of NF-kB signaling and improves survival in mouse models of sepsis. Acta Pharmacol Sin 33(9):1204–1216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122(3):787–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25(6):280–288

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Author notes

  1. Xujing Liang and Taoyuan Li have contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Disease, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Xujing Liang, Taoyuan Li, Sainan Pi & Youpeng Chen

  2. Institute of Laboratory Animal Science, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Qiuchan Zhou

  3. Institute of Biomedicine, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Yadan Li, Xiaojia Chen & Ying Zhao

  4. Department of Pathology, The First Affiliated Hospital, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Zeping Weng

  5. Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510630, Guangdong, People’s Republic of China

    Hongmei Li & Huadong Wang

Authors
  1. Xujing Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taoyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qiuchan Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sainan Pi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yadan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaojia Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zeping Weng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongmei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ying Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Huadong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Youpeng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huadong Wang or Youpeng Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 1276 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liang, X., Li, T., Zhou, Q. et al. Mesenchymal stem cells attenuate sepsis-induced liver injury via inhibiting M1 polarization of Kupffer cells. Mol Cell Biochem 452, 187–197 (2019). https://doi.org/10.1007/s11010-018-3424-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3424-7

Keywords

Search

Navigation