Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells.
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.
Boitano
Anthony E
AE
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Wang
Jian
J
Romeo
Russell
R
Bouchez
Laure C
LC
Parker
Albert E
AE
Sutton
Sue E
SE
Walker
John R
JR
Flaveny
Colin A
CA
Perdew
Gary H
GH
Denison
Michael S
MS
Schultz
Peter G
PG
Cooke
Michael P
MP
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D065633:Cytochrome P-450 CYP1B1; D016207:Cytokines / Q000494:pharmacology; D006023:Glycoproteins / Q000032:analysis; D006410:Hematopoiesis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D039902:Multipotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000032:analysis; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D011687:Purines / Q000378:metabolism* / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries; D013045:Species Specificity
D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D016207:Cytokines; D006023:Glycoproteins; D010455:Peptides; D000072317:Polychlorinated Dibenzodioxins; D011687:Purines; D018336:Receptors, Aryl Hydrocarbon; D054852:Small Molecule Libraries; C552240:StemRegenin 1; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1