title: Inverse regulation of early and late chondrogenic differentiation by oxygen tension provides cues for stem cell-based cartilage tissue engineering.
abstract: OBJECTIVE
  Multipotent stem/stromal cells (MSC) are considered promising for cartilage tissue engineering. However, chondrogenic differentiation of MSC can ultimately lead to the formation of hypertrophic chondrocytes responsible for the calcification of cartilage. To prevent the production of this calcified matrix at the articular site, the late hypertrophic differentiation of MSCs must be carefully controlled. Given that articular cartilage is avascular, we hypothesized that in addition to its stimulatory role in the early differentiation of chondrogenic cells, hypoxia may prevent their late hypertrophic conversion.
  
  
  METHODS
  Early and late chondrogenic differentiation were evaluated using human adipose MSC and murine ATDC5 cells cultured under either normoxic (21%O2) or hypoxic (5%O2) conditions. To investigate the effect of hypoxia on late chondrogenic differentiation, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1α) and HIF-2α were evaluated using the NoShift DNA-binding assay and through modulation of their activity (chemical inhibitor, RNA interference). Results : Our data demonstrate that low oxygen tension not only stimulates the early chondrogenic commitment of two complementary models of chondrogenic cells, but also inhibits their hypertrophic differentiation. Conclusion : These results suggest that hypoxia can be used as an instrumental tool to prevent the formation of a calcified matrix in MSC-based cartilage tissue engineering.
authors: INSERM (Institut National de la Santé et de la Recherche Médicale), UMRS 791, Center for osteoarticular and dental tissue engineering, Group STEP "Skeletal Tissue Engineering and Physiopathology", Nantes Cedex 1, France.
authors: Sophie
authors: S
authors: Portron
authors: Vincent
authors: V
authors: Hivernaud
authors: Christophe
authors: C
authors: Merceron
authors: Julie
authors: J
authors: Lesoeur
authors: Martial
authors: M
authors: Masson
authors: Olivier
authors: O
authors: Gauthier
authors: Claire
authors: C
authors: Vinatier
authors: Laurent
authors: L
authors: Beck
authors: Jérôme
authors: J
authors: Guicheux
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D002114:Calcinosis / Q000235:genetics / Q000473:pathology; D002358:Cartilage, Articular / Q000166:cytology / Q000254:growth & development*; D002454:Cell Differentiation / Q000235:genetics*; D015687:Cell Hypoxia; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010100:Oxygen / Q000378:metabolism; D023822:Tissue Engineering
chemical_list: C497396:ARNT protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D010100:Oxygen