Differential Regulation of Human Bone Marrow Mesenchymal Stromal Cell Chondrogenesis by Hypoxia Inducible Factor-1α Hydroxylase Inhibitors.

Details

Serval ID
serval:BIB_676A9E4E6910
Type
Article: article from journal or magazin.
Collection
Publications
Title
Differential Regulation of Human Bone Marrow Mesenchymal Stromal Cell Chondrogenesis by Hypoxia Inducible Factor-1α Hydroxylase Inhibitors.
Journal
Stem cells
Author(s)
Taheem D.K., Foyt D.A., Loaiza S., Ferreira S.A., Ilic D., Auner H.W., Grigoriadis A.E., Jell G., Gentleman E.
ISSN
1549-4918 (Electronic)
ISSN-L
1066-5099
Publication state
Published
Issued date
09/2018
Peer-reviewed
Oui
Volume
36
Number
9
Pages
1380-1392
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The transcriptional profile induced by hypoxia plays important roles in the chondrogenic differentiation of marrow stromal/stem cells (MSC) and is mediated by the hypoxia inducible factor (HIF) complex. However, various compounds can also stabilize HIF's oxygen-responsive element, HIF-1α, at normoxia and mimic many hypoxia-induced cellular responses. Such compounds may prove efficacious in cartilage tissue engineering, where microenvironmental cues may mediate functional tissue formation. Here, we investigated three HIF-stabilizing compounds, which each have distinct mechanisms of action, to understand how they differentially influenced the chondrogenesis of human bone marrow-derived MSC (hBM-MSC) in vitro. hBM-MSCs were chondrogenically-induced in transforming growth factor-β3-containing media in the presence of HIF-stabilizing compounds. HIF-1α stabilization was assessed by HIF-1α immunofluorescence staining, expression of HIF target and articular chondrocyte specific genes by quantitative polymerase chain reaction, and cartilage-like extracellular matrix production by immunofluorescence and histochemical staining. We demonstrate that all three compounds induced similar levels of HIF-1α nuclear localization. However, while the 2-oxoglutarate analog dimethyloxalylglycine (DMOG) promoted upregulation of a selection of HIF target genes, desferrioxamine (DFX) and cobalt chloride (CoCl <sub>2</sub> ), compounds that chelate or compete with divalent iron (Fe <sup>2+</sup> ), respectively, did not. Moreover, DMOG induced a more chondrogenic transcriptional profile, which was abolished by Acriflavine, an inhibitor of HIF-1α-HIF-β binding, while the chondrogenic effects of DFX and CoCl <sub>2</sub> were more limited. Together, these data suggest that HIF-1α function during hBM-MSC chondrogenesis may be regulated by mechanisms with a greater dependence on 2-oxoglutarate than Fe <sup>2+</sup> availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. Stem Cells 2018;36:1380-1392.
Keywords
Amino Acids, Dicarboxylic/pharmacology, Bone Marrow Cells/cytology, Bone Marrow Cells/drug effects, Bone Marrow Cells/metabolism, Cell Differentiation/drug effects, Cell Hypoxia/drug effects, Cell Hypoxia/physiology, Child, Chondrogenesis/drug effects, Cobalt/pharmacology, Deferoxamine/pharmacology, Enzyme Inhibitors/pharmacology, Humans, Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit/metabolism, Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors, Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism, Mesenchymal Stem Cells/cytology, Mesenchymal Stem Cells/drug effects, Mesenchymal Stem Cells/metabolism, Bone marrow stromal cells (BMSCs), Cell signaling, Chondrogenesis, Differentiation, Hypoxia, Mesenchymal stem cells (MSCs), Tissue regeneration
Pubmed
Web of science
Open Access
Yes
Create date
12/01/2024 11:14
Last modification date
13/01/2024 8:10
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