Open AccessDifferential Regulation of Human Bone Marrow Mesenchymal Stromal Cell Chondrogenesis by Hypoxia Inducible Factor‐1α Hydroxylase Inhibitors
Author(s) -
Taheem Dheraj K.,
Foyt Daniel A.,
Loaiza Sandra,
Ferreira Silvia A.,
Ilic Dusko,
Auner Holger W.,
Grigoriadis Agamem E.,
Jell Gavin,
Gentleman Eileen
Publication year - 2018
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.2844
Subject(s) - chondrogenesis , mesenchymal stem cell , biology , microbiology and biotechnology , stromal cell , chondrocyte , hypoxia inducible factors , bone marrow , downregulation and upregulation , cartilage , biochemistry , immunology , cancer research , anatomy , gene
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 2 ), compounds that chelate or compete with divalent iron (Fe 2+ ), 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 2 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 2+ availability. These results may have important implications for understanding cartilage disease and developing targeted therapies for cartilage repair. S tem C ells 2018;36:1380–1392