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

Science, 10 September 2010
Vol. 329, Issue 5997, p. 1345-1348
DOI: 10.1126/science.1191536

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

  1. Anthony E. Boitano1,2,
  2. Jian Wang1,
  3. Russell Romeo2,
  4. Laure C. Bouchez1,
  5. Albert E. Parker2,
  6. Sue E. Sutton2,
  7. John R. Walker2,
  8. Colin A. Flaveny3,
  9. Gary H. Perdew3,
  10. Michael S. Denison4,
  11. Peter G. Schultz1,*,
  12. Michael P. Cooke2,*
  1. 1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
  2. 2Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
  3. 3The Pennsylvania State University, University Park, PA 16803, USA.
  4. 4University of California, Davis, One Shields Avenue, Davis, CA 95616, USA.
  1. *To whom correspondence should be addressed. E-mail: schultz{at}scripps.edu (P.G.S.); mcooke{at}gnf.org (M.P.C.)

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.

  • Received for publication 27 April 2010.
  • Accepted for publication 7 July 2010.

Citation:

A. E. Boitano, J. Wang, R. Romeo, L. C. Bouchez, A. E. Parker, S. E. Sutton, J. R. Walker, C. A. Flaveny, G. H. Perdew, M. S. Denison, P. G. Schultz, and M. P. Cooke, Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells. Science 329, 1345-1348 (2010).

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