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Synergistic effects of simvastatin and bone marrow-derived mesenchymal stem cells on hepatic fibrosis

 Yoon Ok Jang  ;  Sung Hoon Kim  ;  Mee-Yon Cho  ;  Kyung Sik Kim  ;  Kyu-Sang Park  ;  Seung-Kuy Cha  ;  Moon Young Kim  ;  Sei Jin Chang  ;  Soon Koo Baik 
 Biochemical and Biophysical Research Communications, Vol.497(1) : 264-271, 2018 
Journal Title
 Biochemical and Biophysical Research Communications 
Issue Date
Animals ; Bone Marrow Transplantation/*methods ; Cultured Cells ; Combined Modality Therapy/methods ; Drug Synergism ; Liver Cirrhosis/pathology/*physiopathology/*therapy ; Liver Function Tests ; Male ; Mesenchymal Stem Cell Transplantation/*methods ; Rats ; Sprague-Dawley Rats ; Simvastatin/*administration & dosage ; Treatment Outcome
Hepatic fibrosis ; Liver regeneration ; Mesenchymal stem cells ; Simvastatin
The beneficial effects of simvastatin on fibrosis in various organs have been reported. In addition, bone marrow (BM)-derived mesenchymal stem cells (MSCs) have been suggested as an effective therapy for hepatic fibrosis and cirrhosis. Recent evidence suggests that pharmacological treatment devoted to regulating stem cell function is a potential new therapeutic strategy that is drawing nearer to clinical practice. The aim of this study was to determine whether the combination treatment of simvastatin plus MSCs (Sim-MSCs) could have a synergistic effect on hepatic fibrosis in a thioacetamide (TAA)-induced cirrhotic rat model and hepatic stellate cells (HSCs). Cirrhotic livers from rats treated with Sim-MSCs exhibited histological improvement compared to those treated with simvastatin alone. Sim-MSCs combination treatment decreased hepatic collagen distribution, lowered the hydroxyproline content, and rescued liver function impairment in rats with TAA-induced cirrhosis. These protective effects were more potent with Sim-MSCs than with simvastatin alone. The upregulation of collagen-1, alpha-smooth muscle actin (alpha-SMA), transforming growth factor (TGF)-beta1, and phospho-Smad3 in cirrhotic livers was prevented by the administration of Sim-MSCs. Intriguingly, Sim-MSCs inhibited both TGF-beta/Smad3 signaling and alpha-SMA in HSCs. The Sim-MSCs combination treatment exerted strong protective effects against hepatic fibrosis by suppressing TGF-beta/Smad signaling. Simvastatin could act synergistically with MSCs as an efficient therapeutic approach for intractable cirrhosis.
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1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Kyung Sik(김경식) ORCID logo https://orcid.org/0000-0001-9498-284X
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