Mesenchymal Stem Cells And Their Secreted Molecules Ameliorate Liver Injury

Orthotopic liver transplantation is the only effective treatment for liver failure but limited with shortage of available donor organs.Recent studies show promising results of mesenchymal stem cells(MSCs)-based therapies.Here,we systematically investigate the therapeutic effects of MSCs or MSC-conditioned medium(MSC-CM)containing various MSC-secreted soluble factors in ameliorating thioacetimade-and carbon tetrachloride-induced fulminant hepatic failure(FHF)and chronic liver fibrosis in mice.We found that MSCs had a predominate role in ameliorating FHF,as MSC treatment improved survival,whereas MSC-CM only enhanced endogenous repair programs in the late phase of therapy and did not prevent mortality.By contrast,MSC-CM had a predominant role in ameliorating chronic liver fibrosis,with MSC-CM inducing the massive apoptosis of hepatic stellate cells and establishing an anti-inflammatory state.Also,systematical flow cytometry analysis showed that MSCs and their secreted molecules predominantly suppressed inflammatory T helper cells and macrophages in TAA-and CC14-induced mice,and converted the body intoanti-inflammatory state,promoting survival and repair of injury.Both MSCs and MSC-CM exert therapeutic effects by acting on various key cells during the pathogenesis of FHF and chronic fibrosis,stimulating hepatocyte proliferation and suppressing apoptosis,down-regulating infiltrating macrophages,converting the CD4+T lymphocyte system into an anti-inflammatory state,and facilitating hepatic stellate cell death.However,infused-MSCs generate sarcoma after 6 week of MSCs transplants in CC14-stimulated mice,these tumor MSCs lose the potential of adipogenic differentiation and are capable of generating sarcoma.This study represents the first systematic investigation in MSCs and MSC-CM therapy of FHF and chronic liver fibrosis,especially,systematical flow cytometry analysis of spleens from vehicle and MSC-and MSC-CM-treated mice was firstly applied to check the conversion of inflammatory state in different time points of acute liver injury and chronic liver fibrosis.Our findings would provide the clinical doctor with advisable remedies that MSC treatment is more suitable for FHF,whereas delivery of MSC-CM is more suitable for chronic liver fibrosis.