Chemical activation of the hypoxia-inducible factor reversibly reduces tendon stem cell proliferation, inhibits their differentiation, and maintains cell undifferentiation

Alessandra Menon, Pasquale Creo, Marco Piccoli, Sonia Bergante, Erika Conforti, Giuseppe Banfi, Pietro Randelli, Luigi Anastasia

Research output: Contribution to journalArticle

Abstract

Adult stem cell-based therapeutic approaches for tissue regeneration have been proposed for several years. However, adult stem cells are usually limited in number and difficult to be expanded in vitro, and they usually tend to quickly lose their potency with passages, as they differentiate and become senescent. Culturing stem cells under reduced oxygen tensions (below 21%) has been proposed as a tool to increase cell proliferation, but many studies reported opposite effects. In particular, cell response to hypoxia seems to be very stem cell type specific. Nonetheless, it is clear that a major role in this process is played by the hypoxia inducible factor (HIF), the master regulator of cell response to oxygen deprivation, which affects cell metabolism and differentiation. Herein, we report that a chemical activation of HIF in human tendon stem cells reduces their proliferation and inhibits their differentiation in a reversible and dose-dependent manner. These results support the notion that hypoxia, by activating HIF, plays a crucial role in preserving stem cells in an undifferentiated state in the "hypoxic niches" present in the tissue in which they reside before migrating in more oxygenated areas to heal a damaged tissue.

Original languageEnglish
Article number9468085
JournalStem Cells International
Volume2018
DOIs
Publication statusPublished - Jan 1 2018

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Tendons
Cell Differentiation
Stem Cells
Cell Proliferation
Adult Stem Cells
Oxygen
Regeneration
Hypoxia
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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title = "Chemical activation of the hypoxia-inducible factor reversibly reduces tendon stem cell proliferation, inhibits their differentiation, and maintains cell undifferentiation",
abstract = "Adult stem cell-based therapeutic approaches for tissue regeneration have been proposed for several years. However, adult stem cells are usually limited in number and difficult to be expanded in vitro, and they usually tend to quickly lose their potency with passages, as they differentiate and become senescent. Culturing stem cells under reduced oxygen tensions (below 21{\%}) has been proposed as a tool to increase cell proliferation, but many studies reported opposite effects. In particular, cell response to hypoxia seems to be very stem cell type specific. Nonetheless, it is clear that a major role in this process is played by the hypoxia inducible factor (HIF), the master regulator of cell response to oxygen deprivation, which affects cell metabolism and differentiation. Herein, we report that a chemical activation of HIF in human tendon stem cells reduces their proliferation and inhibits their differentiation in a reversible and dose-dependent manner. These results support the notion that hypoxia, by activating HIF, plays a crucial role in preserving stem cells in an undifferentiated state in the {"}hypoxic niches{"} present in the tissue in which they reside before migrating in more oxygenated areas to heal a damaged tissue.",
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AU - Menon, Alessandra

AU - Creo, Pasquale

AU - Piccoli, Marco

AU - Bergante, Sonia

AU - Conforti, Erika

AU - Banfi, Giuseppe

AU - Randelli, Pietro

AU - Anastasia, Luigi

PY - 2018/1/1

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N2 - Adult stem cell-based therapeutic approaches for tissue regeneration have been proposed for several years. However, adult stem cells are usually limited in number and difficult to be expanded in vitro, and they usually tend to quickly lose their potency with passages, as they differentiate and become senescent. Culturing stem cells under reduced oxygen tensions (below 21%) has been proposed as a tool to increase cell proliferation, but many studies reported opposite effects. In particular, cell response to hypoxia seems to be very stem cell type specific. Nonetheless, it is clear that a major role in this process is played by the hypoxia inducible factor (HIF), the master regulator of cell response to oxygen deprivation, which affects cell metabolism and differentiation. Herein, we report that a chemical activation of HIF in human tendon stem cells reduces their proliferation and inhibits their differentiation in a reversible and dose-dependent manner. These results support the notion that hypoxia, by activating HIF, plays a crucial role in preserving stem cells in an undifferentiated state in the "hypoxic niches" present in the tissue in which they reside before migrating in more oxygenated areas to heal a damaged tissue.

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