Mesenchymal stem cells and Interleukin-6 attenuate liver fibrosis in mice

J Transl Med. 2013 Mar 26;11:78. doi: 10.1186/1479-5876-11-78.

Abstract

Background: Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for liver fibrosis. Issues concerning poor MSC survival and engraftment in the fibrotic liver still persist and warrant development of a strategy to increase MSC potency for liver repair. The present study was designed to examine a synergistic role for Interleukin-6 (IL-6) and MSCs therapy in the recovery of carbon tetrachloride (CCl(4)) induced injured hepatocytes in vitro and in vivo.

Methods: Injury was induced through 3 mM and 5 mM CCl(4) treatment of cultured hepatocytes while fibrotic mouse model was established by injecting 0.5 ml/kg CCl(4) followed by treatment with IL-6 and MSCs. Effect of MSCs and IL-6 treatment on injured hepatocytes was determined by lactate dehydrogenase release, RT-PCR for (Bax, Bcl-xl, Caspase3, Cytokeratin 8, NFκB, TNF-α) and annexin V apoptotic detection. Analysis of MSC and IL-6 treatment on liver fibrosis was measured by histopathology, PAS, TUNEL and Sirius red staining, RT-PCR, and liver function tests for Bilirubin and Alkaline Phosphatase (ALP).

Results: A significant reduction in LDH release and apoptosis was observed in hepatocytes treated with a combination of MSCs and IL-6 concomitant with upregulation of anti-apoptotic gene Bcl-xl expression and down regulation of bax, caspase3, NFκB and TNF-α. Adoptive transfer of MSCs in fibrotic liver pretreated with IL-6 resulted increased MSCs homing and reduced fibrosis and apoptosis. Hepatic functional assessment demonstrated reduced serum levels of Bilirubin and ALP.

Conclusion: Pretreatment of fibrotic liver with IL-6 improves hepatic microenvironment and primes it for MSC transplantation leading to enhanced reduction of liver injury after fibrosis. Synergistic effect of IL-6 and MSCs seems a favored therapeutic option in attenuation of liver apoptosis and fibrosis accompanied by improved liver function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carbon Tetrachloride / pharmacology
  • Coculture Techniques
  • Female
  • Gene Expression Regulation*
  • Glycogen / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Inflammation
  • Interleukin-6 / metabolism*
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / therapy*
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology*
  • Mice
  • Mice, Inbred C57BL

Substances

  • Interleukin-6
  • Glycogen
  • Carbon Tetrachloride