Differential regulation of human bone marrow mesenchymal stromal cell chondrogenesis by hypoxia inducible factor-1α hydroxylase inhibitors
File(s)
Published version
OA Location
Author(s)
Type
Journal Article
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 complex. However, various compounds can also stabilise 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 stabilising 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 TGF-β3 -containing media in the presence of HIF-stabilising compounds. HIF-1α stabilisation was assessed by HIF-1α immunofluorescence staining, expression of HIF target and articular chondrocyte specific genes by qPCR, and cartilage-like extracellular matrix (ECM) production by immunofluorescence and histochemical staining. We demonstrate that all three compounds induced similar levels of HIF-1α nuclear localisation. However, whilst the 2-oxoglutarate analogue Dimethyloxalylglycine (DMOG) promoted upregulation of a selection of HIF target genes, Desferrioxamine (DFX) and Cobalt Chloride (CoCl2 ), compounds that chelate or compete with Fe2+ , respectively, did not. Moreover, DMOG induced a more chondrogenic transcriptional profile, which was abolished by Acriflavine, an inhibitor of HIF-1α-HIF-β binding, whilst the chondrogenic effects of DFX and CoCl2 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 Fe2+ availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. This article is protected by copyright. All rights reserved.
Date Issued
2018-09-01
Date Acceptance
2018-04-22
Citation
Stem Cells, 2018, 36 (9), pp.1380-1392
ISSN
1066-5099
Publisher
AlphaMed Press
Start Page
1380
End Page
1392
Journal / Book Title
Stem Cells
Volume
36
Issue
9
Copyright Statement
© 2018 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/).
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited (http://creativecommons.org/licenses/by/4.0/).
Sponsor
CRUK
Cancer Research UK
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/29726060
Grant Number
C41494/A15448
15448
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell & Tissue Engineering
Biotechnology & Applied Microbiology
Oncology
Cell Biology
Hematology
Bone marrow stromal cells (BMSCs)
Cell signaling
Chondrogenesis
Differentiation
Hypoxia
Mesenchymal stem cells (MSCs)
Tissue regeneration
GENE-EXPRESSION
FACTOR-I
STEM-CELLS
HIF-1-ALPHA
COLLAGEN
CARTILAGE
GROWTH
DESFERRIOXAMINE
SCAFFOLDS
AGGRECAN
Bone marrow stromal cells (BMSCs)
Cell signaling
Chondrogenesis
Differentiation
Hypoxia
Mesenchymal stem cells (MSCs)
Tissue regeneration
Immunology
06 Biological Sciences
10 Technology
11 Medical and Health Sciences
Publication Status
Published online
Coverage Spatial
United States
Date Publish Online
2018-05-03