Chromatin remodeling agent trichostatin A: a key-factor in the hepatic differentiation of human mesenchymal stem cells derived of adult bone marrow.
BACKGROUND
The capability of human mesenchymal stem cells (hMSC) derived of adult bone marrow to undergo in vitro hepatic differentiation was investigated.


RESULTS
Exposure of hMSC to a cocktail of hepatogenic factors [(fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF), insulin-transferrin-sodium-selenite (ITS) and dexamethasone)] failed to induce hepatic differentiation. Sequential exposure to these factors (FGF-4, followed by HGF, followed by HGF+ITS+dexamethasone), however, resembling the order of secretion during liver embryogenesis, induced both glycogen-storage and cytokeratin (CK)18 expression. Additional exposure of the cells to trichostatin A (TSA) considerably improved endodermal differentiation, as evidenced by acquisition of an epithelial morphology, chronological expression of hepatic proteins, including hepatocyte-nuclear factor (HNF)-3beta, alpha-fetoprotein (AFP), CK18, albumin (ALB), HNF1alpha, multidrug resistance-associated protein (MRP)2 and CCAAT-enhancer binding protein (C/EBP)alpha, and functional maturation, i.e. upregulated ALB secretion, urea production and inducible cytochrome P450 (CYP)-dependent activity.


CONCLUSIONS
hMSC are able to undergo mesenchymal-to-epithelial transition. TSA is hereby essential to promote differentiation of hMSC towards functional hepatocyte-like cells.
Snykers
Sarah
S
Dept. Toxicology, Vrije Universiteit Brussel, Laarbeeklaan 103, B-1090, Brussels, Belgium. Sarah.Snykers@vub.ac.be
Vanhaecke
Tamara
T
De Becker
Ann
A
Papeleu
Peggy
P
Vinken
Mathieu
M
Van Riet
Ivan
I
Rogiers
Vera
V
D000107:Acetylation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001854:Bone Marrow Cells / Q000166:cytology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D022781:Hepatocytes / Q000166:cytology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D016130:Immunophenotyping; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2
C000715087:ABCC2 protein, human; D006657:Histones; D006877:Hydroxamic Acids; D000089762:Multidrug Resistance-Associated Protein 2; C012589:trichostatin A