Home LiteratureArticle Details

PMID: 20688981 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

Science (New York, N.Y.) ·Vol. 329 ·No. 5997 ·2010-09-10 ·Pages 1345-8

Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP

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.

MeSH Terms

AC133 Antigen Animals Antigens, CD/analysis Antigens, CD34/analysis Aryl Hydrocarbon Hydroxylases/genetics,metabolism Cell Count Cell Lineage Cell Proliferation Cells, Cultured Cytochrome P-450 CYP1B1 Cytokines/pharmacology Glycoproteins/analysis Hematopoiesis Hematopoietic Stem Cell Transplantation Hematopoietic Stem Cells/cytology,drug effects,metabolism,physiology Humans Mice Mice, Inbred NOD Mice, SCID Multipotent Stem Cells/cytology,drug effects,physiology Peptides/analysis Polychlorinated Dibenzodioxins/pharmacology Purines/metabolism,pharmacology Receptors, Aryl Hydrocarbon/antagonists & inhibitors,metabolism Signal Transduction Small Molecule Libraries Species Specificity

Chemicals

AC133 Antigen Antigens, CD Antigens, CD34 Cytokines Glycoproteins Peptides Polychlorinated Dibenzodioxins Purines Receptors, Aryl Hydrocarbon Small Molecule Libraries StemRegenin 1 Aryl Hydrocarbon Hydroxylases CYP1B1 protein, human Cyp1b1 protein, mouse Cytochrome P-450 CYP1B1

Authors & Affiliations

12 authors, click to expand affiliations / ORCID

Boitano Anthony E

Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Wang Jian

Romeo Russell

Bouchez Laure C

Parker Albert E

Sutton Sue E

Walker John R

Flaveny Colin A

Perdew Gary H

Denison Michael S

Schultz Peter G

Cooke Michael P

References (24)

24 references, click to expand

Phenotypic and functional characterization of hematopoietic stem cells.
Curr Opin Hematol. 2008 Jul;15(4):293-300 PMID: 18536565
Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals.
Fundam Appl Toxicol. 1996 Apr;30(2):194-203 PMID: 8812265
Ligand selectivity and gene regulation by the human aryl hydrocarbon receptor in transgenic mice.
Mol Pharmacol. 2009 Jun;75(6):1412-20 PMID: 19299563
Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis.
Nature. 2007 Jun 21;447(7147):1007-11 PMID: 17581586
Biology of hematopoietic stem cells and progenitors: implications for clinical application.
Annu Rev Immunol. 2003;21:759-806 PMID: 12615892
Expanding the role of umbilical cord blood transplantation.
Br J Haematol. 2007 Apr;137(1):20-35 PMID: 17359369
A combinatorial scaffold approach toward kinase-directed heterocycle libraries.
J Am Chem Soc. 2002 Feb 27;124(8):1594-6 PMID: 11853431
Treatment of mice with the Ah receptor agonist and human carcinogen dioxin results in altered numbers and function of hematopoietic stem cells.
Carcinogenesis. 2009 Jan;30(1):11-9 PMID: 18820284
Antiteratogenic effects of alpha-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed mice in utero.
Reprod Toxicol. 2007 Nov-Dec;24(3-4):303-9 PMID: 17889503
TCDD treatment eliminates the long-term reconstitution activity of hematopoietic stem cells.
Toxicol Sci. 2003 Mar;72(1):84-91 PMID: 12604837
Ex vivo expansion of umbilical cord blood stem cells for transplantation: growing knowledge from the hematopoietic niche.
Bone Marrow Transplant. 2007 Jan;39(1):11-23 PMID: 17164824
Surface fucosylation of human cord blood cells augments binding to P-selectin and E-selectin and enhances engraftment in bone marrow.
Blood. 2004 Nov 15;104(10):3091-6 PMID: 15280192
Inhibition of CD26 in human cord blood CD34+ cells enhances their engraftment of nonobese diabetic/severe combined immunodeficiency mice.
Stem Cells Dev. 2007 Jun;16(3):347-54 PMID: 17610364
Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primitive CD34+ Thy-1+ cells into rapid division.
Exp Hematol. 1999 Jun;27(6):1019-28 PMID: 10378891
Definition of a dioxin receptor mutant that is a constitutive activator of transcription: delineation of overlapping repression and ligand binding functions within the PAS domain.
J Biol Chem. 2001 Nov 9;276(45):41841-9 PMID: 11551926
NOD/SCID/gamma(c)(null) mouse: an excellent recipient mouse model for engraftment of human cells.
Blood. 2002 Nov 1;100(9):3175-82 PMID: 12384415
Unrelated cord blood transplantation vs matched unrelated donor bone marrow transplantation: the risks and benefits of each choice.
Bone Marrow Transplant. 2000 May;25 Suppl 2:S58-60 PMID: 10933191
Microarray analysis of the AHR system: tissue-specific flexibility in signal and target genes.
Toxicol Appl Pharmacol. 2007 May 1;220(3):320-32 PMID: 17350064
Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies.
Clin Pharmacol Ther. 2007 Sep;82(3):252-64 PMID: 17671448
The aryl hydrocarbon receptor has a normal function in the regulation of hematopoietic and other stem/progenitor cell populations.
Biochem Pharmacol. 2009 Feb 15;77(4):577-87 PMID: 18983985
Novel compound 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191) prevents 2,3,7,8-TCDD-induced toxicity by antagonizing the aryl hydrocarbon receptor.
Mol Pharmacol. 2006 Jun;69(6):1871-8 PMID: 16540597
Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.
Blood. 2002 Sep 1;100(5):1611-8 PMID: 12176879
Ex vivo expansion of cord blood.
Bone Marrow Transplant. 2009 Nov;44(10):673-81 PMID: 19802023
Alternative haematopoietic stem cell sources for transplantation: place of umbilical cord blood.
Br J Haematol. 2009 Oct;147(2):246-61 PMID: 19796274

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

1095-9203

DOI

10.1126/science.1191536

Published

2010-09-10

Epub

2010-00-05

Pages

1345-8

Language

English

Region

United States

NLM ID

0404511

PMCID

PMC3033342

Subset

Grants

NIEHS NIH HHS · R01 ES007685 · United States

NIEHS NIH HHS · ES007685 · United States

NIEHS NIH HHS · P42 ES004699 · United States

NIEHS NIH HHS · R01 ES004869-23 · United States

NIEHS NIH HHS · ES04699 · United States

NIEHS NIH HHS · ES004869 · United States

NIEHS NIH HHS · R01 ES004869 · United States

NIEHS NIH HHS · P42 ES004699-24 · United States

NIEHS NIH HHS · R01 ES007685-11 · United States

Corrections

ErratumIn

CommentIn

PMID: 20829472

External Links

PubMed source DOI: 10.1126/science.1191536 PMC Full Text View journal details

Analysis Services

Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.

Contact

WeChat Official Account