title: Bone marrow-derived mesenchymal stem cells effectively regenerate fibrotic liver in bile duct ligation rat model.
abstract: Mesenchymal stem cells (MSCs) have attracted lots of attention for the treatment of acute liver failure and end-stage liver diseases. This study aimed at investigating the fundamental mechanism by which bone marrow-derived MSCs (BM-MSCs) induce liver regeneration of fibrotic liver in rats. Rats underwent bile duct ligation (BDL) surgery and four weeks later they were treated with either BM-MSCs (3 × 10(6) cells /rat, once, tail vein injection) or silymarin (100 mg/kg, daily, orally) for four weeks. Liver function tests and hepatic oxidative stress were determined. Hepatic injury and fibrosis were assessed by H and E, Sirus red staining and immunohistochemical expression of α-smooth muscle actin (α-SMA). Hepatocyte growth factor (HGF) and the gene expression of cytokeratin-19 (CK-19) and matrix metalloproteinase-2 (MMP-2) in liver tissue were determined. BDL induced cholestatic liver injury characterized by elevated ALT and AST activities, bilirubin and decreased albumin. The architecture damage was staged as Metavir score: F3, A3. Fibrosis increased around proliferating bile duct as indicated by sirus red staining and α-SMA immunostaining. Fibrogenesis was favored over fibrolysis and confirmed by decreased HGF with increased expression of CK-19, but decreased MMP-2 expression. BM-MSCs treatment restored deteriorated liver functions and restored the histological changes, resolved fibrosis by improving liver regenerative capabilities (P < 0.001), increases in HGF and MMP-2 mRNA and downregulating CK-19 mRNA. Sliymarin, however, induced similar but less prominent effects compared to BM-MSCs. In conclusion, liver regenerative capabilities can be stimulated by BM-MSCs via augmentation of HGF that subsequently up-regulate MMP-2 mRNA while downregulating CK-19 mRNA.
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt hodael_sayed@yahoo.com.
authors.forename: Hoda E
authors.initials: HE
authors.lastname: Mohamed
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Sahar E
authors.initials: SE
authors.lastname: Elswefy
authors.affiliation: Department of Medical Biochemistry, Unit of Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo 11562, Egypt.
authors.forename: Laila A
authors.initials: LA
authors.lastname: Rashed
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Nahla N
authors.initials: NN
authors.lastname: Younis
authors.affiliation: Histology and Cell Biology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Shaheen
authors.affiliation: Biochemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
authors.forename: Amal M H
authors.initials: AM
authors.lastname: Ghanim
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001652:Bile Ducts; D001853:Bone Marrow; D004195:Disease Models, Animal; D008026:Ligation; D008099:Liver / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000473:pathology / Q000628:therapy*; D008111:Liver Function Tests; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D018384:Oxidative Stress; D020011:Protective Agents / Q000008:administration & dosage; D017208:Rats, Wistar; D012838:Silymarin / Q000008:administration & dosage; D033581:Stem Cell Transplantation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D020011:Protective Agents; D012838:Silymarin
keywords: Bone marrow-derived mesenchymal stem cells; bile duct ligation; cytokeratin-19; hepatic regeneration; hepatocyte growth factor; matrix mettaloproteinase-2
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