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PMID: 16857736 Published · ppublish English Journal Article

Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 103 ·No. 31 ·2006-08-01 ·Pages 11707-12

Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, McDonnell DP

Abstract

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.

MeSH Terms
Aldehyde Dehydrogenase/antagonists & inhibitors,metabolism Aldehyde Dehydrogenase 1 Family 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 Retinal Dehydrogenase Retinoids/metabolism Signal Transduction/physiology Transcription Factors/metabolism p-Aminoazobenzene/analogs & derivatives
Chemicals
Antigens, CD HOXB4 protein, human Homeodomain Proteins Hoxb4 protein, mouse Isoenzymes Retinoids Transcription Factors C.I. Solvent Yellow 56 p-Aminoazobenzene Aldehyde Dehydrogenase 1 Family Aldehyde Dehydrogenase ALDH1A1 protein, human ALDH1A1 protein, mouse Retinal Dehydrogenase
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Chute John P
Division of Cellular Therapy, Duke University Medical Center, Durham, NC 27710, USA. [email protected]
Muramoto Garrett G
Whitesides John
Colvin Michael
Safi Rachid
Chao Nelson J
McDonnell Donald P
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0603806103
Email
[email protected]
Published
2006-08-01
Epub
2006-00-20
Pages
11707-12
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1544234
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.0603806103 PMC Full Text View journal details
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