title: Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions.
abstract: Human adipose tissue-derived multilineage progenitor cells (hADMPCs) are attractive for cell therapy and tissue engineering because of their multipotency and ease of isolation without serial ethical issues. However, their limited in vitro lifespan in culture systems hinders their therapeutic application. Some somatic stem cells, including hADMPCs, are known to be localized in hypoxic regions; thus, hypoxia may be beneficial for ex vivo culture of these stem cells. These cells exhibit a high level of glycolytic metabolism in the presence of high oxygen levels and further increase their glycolysis rate under hypoxia. However, the physiological role of glycolytic activation and its regulatory mechanisms are still incompletely understood. Here, we show that Notch signaling is required for glycolysis regulation under hypoxic conditions. Our results demonstrate that 5% O2 dramatically increased the glycolysis rate, improved the proliferation efficiency, prevented senescence, and maintained the multipotency of hADMPCs. Intriguingly, these effects were not mediated by hypoxia-inducible factor (HIF), but rather by the Notch signaling pathway. Five percent O2 significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2 markedly increased glucose consumption and lactate production of hADMPCs, which decreased back to normoxic levels on treatment with a γ-secretase inhibitor. We also found that HES1 was involved in induction of GLUT3, TPI, and PGK1 in addition to reduction of TIGAR and SCO2 expression. These results clearly suggest that Notch signaling regulates glycolysis under hypoxic conditions and, thus, likely affects the cell lifespan via glycolysis.
authors.affiliation: 1 Pharmaceutical Research and Technology Institute, Kinki University , Higashi-Osaka, Osaka, Japan .
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Moriyama
authors.forename: Mariko
authors.initials: M
authors.lastname: Moriyama
authors.forename: Haruki
authors.initials: H
authors.lastname: Isshi
authors.forename: Shin
authors.initials: S
authors.lastname: Ishihara
authors.forename: Hanayuki
authors.initials: H
authors.lastname: Okura
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ichinose
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ozawa
authors.forename: Akifumi
authors.initials: A
authors.lastname: Matsuyama
authors.forename: Takao
authors.initials: T
authors.lastname: Hayakawa
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D005260:Female; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008875:Middle Aged; D010100:Oxygen / Q000494:pharmacology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051880:Receptors, Notch; D010100:Oxygen