title: Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells.
abstract: BACKGROUND
  Human multipotent mesenchymal stromal cells (MSC) can be isolated from various tissues including bone marrow. Here, MSC participate as bone lining cells in the formation of the hematopoietic stem cell niche. In this compartment, the oxygen tension is low and oxygen partial pressure is estimated to range from 1% to 7%. We analyzed the effect of low oxygen tensions on human MSC cultured with platelet-lysate supplemented media and assessed proliferation, morphology, chromosomal stability, immunophenotype and plasticity.
  
  
  RESULTS
  After transferring MSC from atmospheric oxygen levels of 21% to 1%, HIF-1alpha expression was induced, indicating efficient oxygen reduction. Simultaneously, MSC exhibited a significantly different morphology with shorter extensions and broader cell bodies. MSC did not proliferate as rapidly as under 21% oxygen and accumulated in G1 phase. The immunophenotype, however, was unaffected. Hypoxic stress as well as free oxygen radicals may affect chromosomal stability. However, no chromosomal abnormalities in human MSC under either culture condition were detected using high-resolution matrix-based comparative genomic hybridization. Reduced oxygen tension severely impaired adipogenic and osteogenic differentiation of human MSC. Elevation of oxygen from 1% to 3% restored osteogenic differentiation.
  
  
  CONCLUSIONS
  Physiologic oxygen tension during in vitro culture of human MSC slows down cell cycle progression and differentiation. Under physiological conditions this may keep a proportion of MSC in a resting state. Further studies are needed to analyze these aspects of MSC in tissue regeneration.
authors.affiliation: Department of General Pediatrics, University Children's Hospital, Tübingen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Holzwarth
authors.forename: Martin
authors.initials: M
authors.lastname: Vaegler
authors.forename: Friederike
authors.initials: F
authors.lastname: Gieseke
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
authors.forename: Gunter
authors.initials: G
authors.lastname: Kerst
authors.forename: Ingo
authors.initials: I
authors.lastname: Müller
mesh_terms: D000293:Adolescent; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D043171:Chromosomal Instability; D005260:Female; D016193:G1 Phase; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D039902:Multipotent Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit