Effect of mesenchymal stem cells administered by two different routes on experimentally induced liver fibrosis in rats

Background:Liver fibrosis is a progressive pathological process involving multiple cellular and molecular events that ultimately lead to deposition of excess matrix proteins in the extracellular space. Adult bone marrow mesenchymal stem cells (BM-MSCs) have the potential to open a new frontier in medicine. BM-derived MSCs can be differentiated into various lineage cells including hepatocyte-like cells. Aim of the work:This study was conducted to investigate the effect of MSCs introduced by two different routes on experimentally induced liver fibrosis in rats.Material and methods:In this study 45 adult male rats were divided into four groups. Fifteen rats served as the control group (group I). In group II (the affected group), 10 rats were injected intraperitoneally with carbon tetrachloride (CCl4; 0.15 ml/100 g body weight) dissolved in an equal volume of castor oil twice a week for 10 weeks. In group III (the intravenous stem cell group), 10 rats were injected intraperitoneally with CCl4 twice a week for 10 weeks and then given a single intravenous dose of MSCs in the sixth week. In group IV (the intrahepatic stem cell group), 10 rats were injected intraperitoneally with CCl4 twice a week for 10 weeks and then administered a single intrahepatic MSC dose in the sixth week. Liver samples were taken after 10 weeks from the first dose of CCl4 for processing of paraffin sections and for staining with H E, Sirius red, and immunohistochemistry staining for detection of matrix metalloproteinase-13 (MMP-13) and tissue inhibitors of matrix metalloproteases-1 (TIMP-1). The slides stained by Sirius red were quantitatively analyzed for collagen fibers. Results:CCl4 induced liver necrosis and fibrosis after 10 weeks (ballooning of hepatocytes, moderate-to-severe cytoplasmic vacuolation, massive accumulation of collagen fibers, weak expression of MMP-13, and strong expression of TIMP-1). Intrahepatic MSCs reduced the impact of CCl4 on the liver more than those injected by the intravenous route (minimal cytoplasmic vacuolation of hepatocytes, significant decrease in collagen fiber accumulation, strong expression of MMP-13, and weak expression of TIMP-1). Conclusion:BM-derived MSCs can improve liver fibrosis, and the route of transplantation affects the results. The intrahepatic route is better than the intravenous route in reducing the hepatic necrosis and fibrosis induced by CCl4.