Document Detail


Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.
MedLine Citation:
PMID:  16857736     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aldehyde dehydrogenase (ALDH) is an enzyme that is expressed in the liver and is required for the conversion of retinol (vitamin A) to retinoic acids. ALDH is also highly enriched in hematopoietic stem cells (HSCs) and is considered a selectable marker of human HSCs, although its contribution to stem cell fate remains unknown. In this study, we demonstrate that ALDH is a key regulator of HSC differentiation. Inhibition of ALDH with diethylaminobenzaldehyde (DEAB) delayed the differentiation of human HSCs that otherwise occurred in response to cytokines. Moreover, short-term culture with DEAB caused a 3.4-fold expansion in the most primitive assayable human cells, the nonobese diabetic/severe combined immunodeficiency mouse repopulating cells, compared with day 0 CD34(+)CD38(-)lin(-) cells. The effects of DEAB on HSC differentiation could be reversed by the coadministration of the retinoic acid receptor agonist, all-trans-retinoic acid, suggesting that the ability of ALDH to generate retinoic acids is important in determining HSC fate. DEAB treatment also caused a decrease in retinoic acid receptor-mediated signaling within human HSCs, suggesting directly that inhibition of ALDH promotes HSC self-renewal via reduction of retinoic acid activity. Modulation of ALDH activity and retinoid signaling is a previously unrecognized and effective strategy to amplify human HSCs.
Authors:
John P Chute; Garrett G Muramoto; John Whitesides; Michael Colvin; Rachid Safi; Nelson J Chao; Donald P McDonnell
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Publication Detail:
Type:  Journal Article     Date:  2006-07-20
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  103     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2006 Aug 
Date Detail:
Created Date:  2006-08-02     Completed Date:  2006-10-25     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11707-12     Citation Subset:  IM    
Affiliation:
Division of Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA. john.chute@duke.edu
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MeSH Terms
Descriptor/Qualifier:
Aldehyde Dehydrogenase / antagonists & inhibitors*,  metabolism
Animals
Antigens, CD / metabolism
Cell Differentiation / physiology*
Cells, Cultured
Hematopoietic Stem Cells / cytology,  physiology*
Homeodomain Proteins / metabolism
Humans
Isoenzymes / antagonists & inhibitors*,  metabolism
Mice
Mice, SCID
Retinoids / metabolism*
Signal Transduction / physiology*
Transcription Factors / metabolism
p-Aminoazobenzene / analogs & derivatives
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/HOXB4 protein, human; 0/Homeodomain Proteins; 0/Hoxb4 protein, mouse; 0/Isoenzymes; 0/Retinoids; 0/Transcription Factors; 2481-94-9/C.I. Solvent Yellow 56; 60-09-3/p-Aminoazobenzene; EC 1.2.1.-/aldehyde dehydrogenase 1; EC 1.2.1.3/Aldehyde Dehydrogenase
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