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J. Biol. Chem., Vol. 281, Issue 41, 30678-30683, October 13, 2006

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Differentiation Arrest by Hypoxia^*

From the Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06510

The stem cell niche is a unique tissue microenvironment that regulates the self-renewal and differentiation of stem cells. Although several stromal cells and molecular pathways have been identified, the microenvironment of the stem cell niche remains largely unclear. Recent evidence suggests that stem cells are localized in areas with low oxygen. We have hypothesized that hypoxia maintains the undifferentiated phenotype of stem/precursor cells. In this report, we demonstrate that hypoxia reversibly arrests preadipocytes in an undifferentiated state. Consistent with this observation, hypoxia maintains the expression of pref-1, a key stem/precursor cell gene that negatively regulates adipogenic differentiation. We further demonstrate that the hypoxia-inducible factor-1 (HIF-1) constitutes an important mechanism for the inhibition of adipogenic differentiation by hypoxia. Our findings suggest that hypoxia in the stem cell niche is critical for the maintenance of the undifferentiated stem or precursor cell phenotype.

Received for publication, May 16, 2006 , and in revised form, August 11, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ These authors contributed equally to this work.

² Current address: Dept. of Biomedical Imaging and Radiological Science, National Yang-Ming University, Taipei 112, Taiwan, China.

³ To whom correspondence should be addressed: Dept. of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St., HRT-313, New Haven, CT 06510. Tel.: 203-737-2183; Fax: 203-785-6309; E-mail: zhong.yun{at}yale.edu.

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