title: Low Oxygen Tension Modulates the Insulin-Like Growth Factor-1 or -2 Signaling via Both Insulin-Like Growth Factor-1 Receptor and Insulin Receptor to Maintain Stem Cell Identity in Placental Mesenchymal Stem Cells.
abstract: Placental mesenchymal stem cells (PMSCs) are readily available multipotent stem cells for potential use in regenerative therapies. For this purpose, PMSCs must be maintained in culture conditions that mimic the in vivo microenvironment. IGFs (IGF-1 and IGF-2) and oxygen tension are low in the placenta in early gestation and increase as pregnancy progresses. IGFs bind to two receptor tyrosine kinases, the IGF-1 receptor (IGF-1R) and the insulin receptor (IR), and their hybrid receptors. We hypothesized that IGF-1 and IGF-2 signal via distinct signaling pathways under low-oxygen tension to maintain PMSC multipotency. In preterm PMSCs, low-oxygen tension increased the expression of IGF-2 and reduced IGF-1. IGF-1 stimulated higher phosphorylation of IGF-1Rβ, ERK1/2, and AKT, which was maintained at steady lower levels by low oxygen tension. PMSC proliferation was increased by IGF-1 more than IGF-2,and was potentiated by low-oxygen tension. This IGF/low oxygen tension-mediated proliferation was receptor dependent because neutralization of the IGF-1R inhibited PMSC proliferation in the presence of IGF-1 and the IR in presence of IGF-2. These findings suggest that both IGF-1R and the IR can participate in mediating IGF signaling in maintaining PMSCs multipotency. We conclude that low-oxygen tension can modify the IGF-1 or IGF-2 signaling via the IGF-1R and IR in PMSCs.
authors.affiliation: Departments of Biochemistry (A.Y., V.K.M.H.) and Paediatrics (V.K.M.H.), Schulich School of Medicine and Dentistry, Children's Health Research Institute (A.Y., V.K.M.H.), and Lawson Health Research Institute (A.Y., V.K.M.H.), Western University, London, Ontario, Canada N6C 2V5.
authors.forename: Amer
authors.initials: A
authors.lastname: Youssef
authors.affiliation: Departments of Biochemistry (A.Y., V.K.M.H.) and Paediatrics (V.K.M.H.), Schulich School of Medicine and Dentistry, Children's Health Research Institute (A.Y., V.K.M.H.), and Lawson Health Research Institute (A.Y., V.K.M.H.), Western University, London, Ontario, Canada N6C 2V5.
authors.forename: Victor K M
authors.initials: VK
authors.lastname: Han
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D015151:Immunoblotting; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D010100:Oxygen; D010920:Placenta / Q000166:cytology / Q000378:metabolism*; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D010100:Oxygen