Effect of bone marrow-derived mesenchymal stem cells on hepatic fibrosisBackground: Cirrhosis, the end stage of progressive hepatic fibrosis, is leading to loss of liver function and the development of hepatocellular carcinoma. Studies from experimental models suggest that bone marrow-derived mesenchymal stem cells (BM-MSCs) have the capacity to differentiate into hepatocytes and exhibit antifibrotic effects.Purpose: The aim of this study was to elucidate the antifibrotic effect of BM-MSCs on hepatic fibrosis in experimental model and patients with cirrhosis.Methods: In pre-clinical studies, we investigated the effect of BM-MSCs to attenuate hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model and to modulate the activation of HSCs indirectly via paracrine stimulation with specific cytokines and growth factors in vitro. As a clinical study, we evaluated the antifibrotic effect of BM-MSCs on alcoholic cirrhosis as a phase II trial.Results: BM-MSCs treated group showed histologically significant improvement of hepatic fibrosis in vivo compared to untreated cirrhotic group (P<0.01). The percentage of collagen proportionate area decreased from 16.7 ± 1.1 to 5.1 ± 0.3 after BM-MSCs treatment (P<0.01). The mRNA levels of TGF-b1, collagen-1, and α-SMA significantly decreased in the BM-MSCs treated group compared to untreated cirrhotic group (P<0.01). The content of hepatic hydroxyproline was significantly lower in the BM-MSCs treatment group compared to untreated cirrhotic group (P<0.01). The protein levels of TGF-b1, α-SMA, Smad2 and Smad3 were decreased in the BM-MSCs treated group compared to untreated cirrhotic group (P<0.01).Indirect coculture of activated HSCs with MSCs decreased the production of TGF-b1 (24.7%) (P<0.01) and IL-6 (8.4%) in vitro (P<0.01). Conversely, coculture of activated HSCs with MSCs increased the production of HGF (33.5%) and IL-10 (31.6%) (P<0.01). HSC viability was decreased by 66% and apoptosis was increased by 43% with direct coculture of activated HSCs with MSCs (P<0.01).In clinical study, according to the Laennec fibrosis system, histological improvements were observed in 6 out of 11 patients (54.5%) after BM-MSCs therapy. The percentage of collagen proportionate area decreased significantly from 22.6 ± 8.4 to 17.7 ± 6.9 after BM-MSCs therapy (P<0.01). The mRNA levels of TGF-b1, collagen-1, and α-SMA were significantly decreased in the BM-MSCs therapy. The MELD score decreased from 9.2 ± 2.8 to 8.3 ± 2.4 after BM-MSCs therapy (P<0.01). The Child-Pugh scores improved in 10 out of 11 patients (90.9%) after BM-MSCs therapy (P<0.01). The other biochemical parameters like ALT, AST, bilirubin and creatinine have been improved after BM-MSCs therapy. No significant complications or side effects were observed during this study.Conclusions: BM-MSCs could attenuate hepatic fibrosis in rats with TAA-induced cirrhosis in vivo. The paracrine effects produced by BM-MSCs were identified by coculture with hepatic stellate cells (HSCs) in vitro. Immunomodulation of HSCs by MSC soluble factors provides the first mechanistic evidence that MSCs could exert a protective role through paracrine signaling to HSCs. In clinical study, BM-MSCs therapy in patient with alcoholic cirrhosis induces a histological and quantitative improvement of hepatic fibrosis. Bone marrow-derived mesenchymal stem cells therapy in cirrhosis is considered as a new strategy for an antifibrosis treatment.