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Stem Cells International
Volume 2018, Article ID 9468085, 13 pages
Research Article

Chemical Activation of the Hypoxia-Inducible Factor Reversibly Reduces Tendon Stem Cell Proliferation, Inhibits Their Differentiation, and Maintains Cell Undifferentiation

1IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy
2IRCCS Istituto Ortopedico Galeazzi, Milan, Italy
3Università Vita-Salute San Raffaele, Milan, Italy
4Azienda Socio Sanitaria Territoriale Centro Specialistico Ortopedico Traumatologico Gaetano Pini-CTO, Milan, Italy
5Department of Biomedical Sciences for Health, University of Milan, Milan, Italy

Correspondence should be addressed to Pietro Randelli; ti.iminu@illednar.orteip and Luigi Anastasia; ti.iminu@aisatsana.igiul

Received 4 September 2017; Accepted 6 December 2017; Published 11 March 2018

Academic Editor: Margherita Maioli

Copyright © 2018 Alessandra Menon et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.