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Hypoxia Inducible Factor-1? Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin ? 4.

ABSTRACT: Although hypoxic environments have been known to regulate the migratory ability of bone marrow-derived mesenchymal stem cells (BM-MSCs), which is a critical factor for maximizing the therapeutic effect, the underlying mechanisms remain unclear. Therefore, we aimed to confirm the effect of hypoxia-inducible factor-1? (HIF-1?) on the migration of BM-MSCs and to analyze the interaction between HIF-1? and integrin-mediated signals. Hypoxia-activated HIF-1? significantly increased BM-MSC migration. The expression of integrin ? 4 was decreased in BM-MSCs by increased HIF-1? under hypoxia, whereas the expression of Rho-associated kinase 1 (ROCK1) and Rac1/2/3 was increased. After downregulation of HIF-1? by YC-1, which is an inhibitor of HIF-1?, BM-MSC migration was decreased via upregulation of integrin ? 4 and downregulation of ROCK1 and Rac1/2/3. Knockdown of integrin ? 4 by integrin ? 4 siRNA (siITGA4) treatment increased BM-MSC migration by upregulation of ROCK1, Rac1/2/3, and matrix metalloproteinase-2 regardless of oxygen tension. Moreover, siITGA4 treatment increased HIF-1? expression and augmented the translocation of HIF-1? into the nucleus under hypoxia. Taken together, the alternative expression of HIF-1? induced by microenvironment factors, such as hypoxia and integrin ? 4, may regulate the migration of BM-MSCs. These findings may provide insights to the underlying mechanisms of BM-MSC migration for successful stem cell-based therapy.

SUBMITTER: Choi JH

PROVIDER: S-EPMC4736322 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Hypoxia Inducible Factor-1α Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin α 4.

Choi Jong Ho JH Lee Yun Bin YB Jung Jieun J Hwang Seong Gyu SG Oh Il-Hoan IH Kim Gi Jin GJ

Stem cells international 20160104

Although hypoxic environments have been known to regulate the migratory ability of bone marrow-derived mesenchymal stem cells (BM-MSCs), which is a critical factor for maximizing the therapeutic effect, the underlying mechanisms remain unclear. Therefore, we aimed to confirm the effect of hypoxia-inducible factor-1α (HIF-1α) on the migration of BM-MSCs and to analyze the interaction between HIF-1α and integrin-mediated signals. Hypoxia-activated HIF-1α significantly increased BM-MSC migration. T ...[more]

PMID: 26880989

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Project description: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 (CoCl2 ), compounds that chelate or compete with divalent iron (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, while 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. Stem Cells 2018;36:1380-1392.

Dataset Information

Hypoxia Inducible Factor-1? Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin ? 4.

Publications

Hypoxia Inducible Factor-1α Regulates the Migration of Bone Marrow Mesenchymal Stem Cells via Integrin α 4.

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