Hypoxia Promotes Osteogenesis but Suppresses Adipogenesis of Human Mesenchymal Stromal Cells in a Hypoxia-Inducible Factor-1 Dependent Manner
| Autor: | M. Hahne, Monique Fangradt, Timo Gaber, Cam Loan Tran, Frank Buttgereit, K Schönbeck, Ferenz Leonard Lohanatha, Paula Hoff, Georg N. Duda, C. Strehl, Carsten Perka, Markus Wagegg, Andrea Ode |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Vascular Endothelial Growth Factor A
Anatomy and Physiology Cellular differentiation Gene Expression Peroxisome proliferator-activated receptor lcsh:Medicine Core Binding Factor Alpha 1 Subunit 0302 clinical medicine Osteogenesis RNA interference Molecular Cell Biology Gene expression lcsh:Science Musculoskeletal System Cells Cultured chemistry.chemical_classification 0303 health sciences Adipogenesis Multidisciplinary Stem Cells Cell Hypoxia Cell biology Vascular endothelial growth factor A Phenotype Gene Knockdown Techniques 030220 oncology & carcinogenesis Medicine RNA Interference Cellular Types medicine.symptom Research Article Transcriptional Activation Biology 03 medical and health sciences Antigens CD medicine Humans Bone 030304 developmental biology Mesenchymal stem cell lcsh:R Mesenchymal Stem Cells Hypoxia (medical) Hypoxia-Inducible Factor 1 alpha Subunit equipment and supplies PPAR gamma chemistry Immunology lcsh:Q Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 9, p e46483 (2012) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0046483 |
| Popis: | BACKGROUND: Bone fracture initiates a series of cellular and molecular events including the expression of hypoxia-inducible factor (HIF)-1. HIF-1 is known to facilitate recruitment and differentiation of multipotent human mesenchymal stromal cells (hMSC). Therefore, we analyzed the impact of hypoxia and HIF-1 on the competitive differentiation potential of hMSCs towards adipogenic and osteogenic lineages. METHODOLOGY/PRINCIPAL FINDINGS: Bone marrow derived primary hMSCs cultured for 2 weeks either under normoxic (app. 18% O(2)) or hypoxic (less than 2% O(2)) conditions were analyzed for the expression of MSC surface markers and for expression of the genes HIF1A, VEGFA, LDHA, PGK1, and GLUT1. Using conditioned medium, adipogenic or osteogenic differentiation as verified by Oil-Red-O or von-Kossa staining was induced in hMSCs under either normoxic or hypoxic conditions. The expression of HIF1A and VEGFA was measured by qPCR. A knockdown of HIF-1α by lentiviral transduction was performed, and the ability of the transduced hMSCs to differentiate into adipogenic and osteogenic lineages was analyzed. Hypoxia induced HIF-1α and HIF-1 target gene expression, but did not alter MSC phenotype or surface marker expression. Hypoxia (i) suppressed adipogenesis and associated HIF1A and PPARG gene expression in hMSCs and (ii) enhanced osteogenesis and associated HIF1A and RUNX2 gene expression. shRNA-mediated knockdown of HIF-1α enhanced adipogenesis under both normoxia and hypoxia, and suppressed hypoxia-induced osteogenesis. CONCLUSIONS/SIGNIFICANCE: Hypoxia promotes osteogenesis but suppresses adipogenesis of human MSCs in a competitive and HIF-1-dependent manner. We therefore conclude that the effects of hypoxia are crucial for effective bone healing, which may potentially lead to the development of novel therapeutic approaches. |
| Databáze: | OpenAIRE |
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