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

被引：816

作者：

Boitano, Anthony E. ^{[1
,2
]}

Wang, Jian ^{[1
]}

Romeo, Russell ^{[2
]}

Bouchez, Laure C. ^{[1
]}

Parker, Albert E. ^{[2
]}

Sutton, Sue E. ^{[2
]}

Walker, John R. ^{[2
]}

Flaveny, Colin A. ^{[3
]}

Perdew, Gary H. ^{[3
]}

Denison, Michael S. ^{[4
]}

Schultz, Peter G. ^{[1
]}

Cooke, Michael P. ^{[2
]}

机构：

[1] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[2] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

[3] Penn State Univ, University Pk, PA 16803 USA

[4] Univ Calif Davis, Davis, CA 95616 USA

来源：

SCIENCE | 2010年 / 329卷 / 5997期

关键词：

UMBILICAL-CORD BLOOD; EX-VIVO EXPANSION; BONE-MARROW; TRANSPLANTATION; ENGRAFTMENT; MICE; BIOLOGY; BINDING;

D O I：

10.1126/science.1191536

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1345 / 1348

页数：4

共 22 条

[1] Expanding the role of umbilical cord blood transplantation [J].

Brunstein, Claudio G. ;

Setubal, Daniela C. ;

Wagner, John E. .

BRITISH JOURNAL OF HAEMATOLOGY, 2007, 137 (01) :20-35

[2] Inhibition of CD26 in human cord blood CD34+ cells enhances their engraftment of nonobese diabetic/severe combined immunodeficiency mice [J].

Campbell, Timothy B. ;

Hangoc, Giao ;

Liu, Ying ;

Pollok, Karen ;

Broxmeyer, Hal E. .

STEM CELLS AND DEVELOPMENT, 2007, 16 (03) :347-353

[3] A combinatorial scaffold approach toward kinase-directed heterocycle libraries [J].

Ding, S ;

Gray, NS ;

Wu, X ;

Ding, Q ;

Schultz, PG .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (08) :1594-1596

[4] Ligand Selectivity and Gene Regulation by the Human Aryl Hydrocarbon Receptor in Transgenic Mice [J].

Flaveny, Colin A. ;

Murray, Iain A. ;

Chiaro, Chris R. ;

Perdew, Gary H. .

MOLECULAR PHARMACOLOGY, 2009, 75 (06) :1412-1420

[5] Microarray analysis of the AHR system: Tissue-specific flexibility in signal and target genes [J].

Frericks, Markus ;

Meissner, Marc ;

Esser, Charlotte .

TOXICOLOGY AND APPLIED PHARMACOLOGY, 2007, 220 (03) :320-332

[6] Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals [J].

Garrison, PM ;

Tullis, K ;

Aarts, JMMJG ;

Brouwer, A ;

Giesy, JP ;

Denison, MS .

FUNDAMENTAL AND APPLIED TOXICOLOGY, 1996, 30 (02) :194-203

[7] Ex vivo expansion of umbilical cord blood stem cells for transplantation:: growing knowledge from the hematopoietic niche [J].

Hofmeister, C. C. ;

Zhang, J. ;

Knight, K. L. ;

Le, P. ;

Stiff, P. J. .

BONE MARROW TRANSPLANTATION, 2007, 39 (01) :11-23

[8] NOD/SCID/γcnull mouse:: an excellent recipient mouse model for engraftment of human cells [J].

Ito, M ;

Hiramatsu, H ;

Kobayashi, K ;

Suzue, K ;

Kawahata, M ;

Hioki, K ;

Ueyama, Y ;

Koyanagi, Y ;

Sugamura, K ;

Tsuji, K ;

Heike, T ;

Nakahata, T .

BLOOD, 2002, 100 (09) :3175-3182

[9] Antiteratogenic effects of α-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed mice in utero [J].

Jang, Ja Young ;

Shin, Sunhee ;

Choi, Byong-Il ;

Park, Dongsun ;

Jeon, Jeong Hee ;

Hwang, Seock-Yeon ;

Kim, Jong-Choon ;

Kim, Yun-Bae ;

Nahm, Sang-Seop .

REPRODUCTIVE TOXICOLOGY, 2007, 24 (3-4) :303-309

[10] Ex vivo expansion of cord blood [J].

Kelly, S. S. ;

Sola, C. B. S. ;

de Lima, M. ;

Shpall, E. .

BONE MARROW TRANSPLANTATION, 2009, 44 (10) :673-681

← 1 2 3 →