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Science 329 (5997): 1345-1348

Copyright © 2010 by the American Association for the Advancement of Science

Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells

Anthony E. Boitano,1,2 Jian Wang,1 Russell Romeo,2 Laure C. Bouchez,1 Albert E. Parker,2 Sue E. Sutton,2 John R. Walker,2 Colin A. Flaveny,3 Gary H. Perdew,3 Michael S. Denison,4 Peter G. Schultz,1,* Michael P. Cooke2,*

Abstract: Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.

1 Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
3 The Pennsylvania State University, University Park, PA 16803, USA.
4 University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.

* To whom correspondence should be addressed. E-mail: schultz{at}scripps.edu (P.G.S.); mcooke{at}gnf.org (M.P.C.)


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