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

Abstract

BackgroundMesenchymal 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 (CCl4) induced injured hepatocytes in vitro and in vivo.MethodsInjury was induced through 3 mM and 5 mM CCl4 treatment of cultured hepatocytes while fibrotic mouse model was established by injecting 0.5 ml/kg CCl4 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).ResultsA 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.ConclusionPretreatment 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.

Untitled

“…39 In addition, MSCs might attenuate hepatic fibrosis through suppression of hepatic stellate cells by the secretion of interleukins 6 and 10. 34,35 In our study, both the hepatocyte-treated and hepatocyte-differentiated MSC-treated groups succeeded in the amelioration of CCl4-induced fibrosis. In agreement with this observation, Badrawy and associates 40 and Nagata and associates, 7 using injected rat hepatocytes, found improved liver fibrosis by formation of hepatocyte sheets in a mouse CCl4 liverinjured model.…”

“…Our results are in agreement with studies that focused on investigating antifibrotic effects on the injured liver in animal models of liver fibrosis. [33][34][35][36] Several mechanisms have been suggested for MSC-mediated improvements in liver function and cirrhosis severity. Mesenchymal stem cells have been shown to be able to produce matrix metalloproteinase, an enzyme capable of degrading the extracellular matrix, which alleviates hepatic cirrhosis directly.…”

Therapeutic Potential of Selenium Treated Stem Cells for the Reduction of Liver Fibrosis

“…PCR base analysis also revealed that the expression of apoptotic markers such as Bax and caspase-3 was high in CCl 4 treated hepatocyte while the expression of hepatocyte markers such as albumin was also inversely proportional to the concentration and duration of CCl 4 treatment [24]. All these markers are the indicator that clearly demonstrates liver fibrosis.…”

Treating end-stage liver diseases with mesenchymal stem cells: An oak is not felled at one stroke

“…HGF may also play a bene icial role in suppressing production of transforming growth factor (TGF)-β, the main player in the pathway activating the HSCs 16,17 . IL-6 and IL-10 may attenuate hepatic ibrosis through suppression of HSCs [18][19][20] . (c) MSCs may dissolve ibrosis directly.…”