Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions

Hiroyuki Moriyama, Mariko Moriyama, Haruki Isshi, Shin Ishihara, Hanayuki Okura, Akihiro Ichinose, Toshiyuki Ozawa, Akifumi Matsuyama, Takao Hayakawa

Research output: Contribution to journalArticle

21 Citations (Scopus)

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% O2dramatically 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 O2significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2markedly 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.

Original languageEnglish
Pages (from-to)2211-2224
Number of pages14
JournalStem Cells and Development
Volume23
Issue number18
DOIs
Publication statusPublished - 01-01-2014

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Glycolysis
Mesenchymal Stromal Cells
Stem Cells
Adipose Tissue
Cell Engineering
Amyloid Precursor Protein Secretases
Adult Stem Cells
Tissue Engineering
Cell- and Tissue-Based Therapy
Ethics
Lactic Acid
Oxygen
Glucose
Therapeutics
Genes
Hypoxia

All Science Journal Classification (ASJC) codes

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Moriyama, Hiroyuki ; Moriyama, Mariko ; Isshi, Haruki ; Ishihara, Shin ; Okura, Hanayuki ; Ichinose, Akihiro ; Ozawa, Toshiyuki ; Matsuyama, Akifumi ; Hayakawa, Takao. / Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions. In: Stem Cells and Development. 2014 ; Vol. 23, No. 18. pp. 2211-2224.
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Moriyama, H, Moriyama, M, Isshi, H, Ishihara, S, Okura, H, Ichinose, A, Ozawa, T, Matsuyama, A & Hayakawa, T 2014, 'Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions', Stem Cells and Development, vol. 23, no. 18, pp. 2211-2224. https://doi.org/10.1089/scd.2013.0642

Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions. / Moriyama, Hiroyuki; Moriyama, Mariko; Isshi, Haruki; Ishihara, Shin; Okura, Hanayuki; Ichinose, Akihiro; Ozawa, Toshiyuki; Matsuyama, Akifumi; Hayakawa, Takao.

In: Stem Cells and Development, Vol. 23, No. 18, 01.01.2014, p. 2211-2224.

Research output: Contribution to journalArticle

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T1 - Role of notch signaling in the maintenance of human mesenchymal stem cells under hypoxic conditions

AU - Moriyama, Hiroyuki

AU - Moriyama, Mariko

AU - Isshi, Haruki

AU - Ishihara, Shin

AU - Okura, Hanayuki

AU - Ichinose, Akihiro

AU - Ozawa, Toshiyuki

AU - Matsuyama, Akifumi

AU - Hayakawa, Takao

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AB - 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% O2dramatically 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 O2significantly increased the level of activated Notch1 and expression of its downstream gene, HES1. Furthermore, 5% O2markedly 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.

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