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.
Highlights
Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for liver fibrosis
Enhanced hepatocyte protection in vitro after MSCs + IL-6 treatment Hepatocytes were subjected to CCl4 treatment (5 mM for 6 hours) followed by treatment with IL-6 for 24 hours
We have demonstrated that IL-6 administration can significantly enhance the ability of MSCs to repair liver after CCl4 induced fibrosis
Summary
Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for liver fibrosis. MSCs have been shown to form functional hepatocytes in vitro [1,2] and possess the ability to secrete soluble factors stimulating endogenous parenchymal cells to support tissue recovery [3,4]. Treatment with bone marrow derived stem cells can attenuate liver fibrosis by preservation of metalloproteinase levels in fibrotic liver [8]. During the course of liver fibrosis different cytokines, chemokines and growth factors are released as part of the inflammatory response Among these secreted factors, IL-6 is a pleiotropic cytokine involved in inflammatory pathways, hematopoiesis and immune regulation. Exogenous IL-6 treatment corrected the defects in cell proliferation in IL-6−/− mice showing its role as mitogenic agent in liver regeneration after partial hepatectomy [12,13]. Positive effects of IL-6 on proliferation and DNA synthesis have been observed on primary hepatocyte cultures [14]
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