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

Publication ,  Journal Article
Chute, JP; Muramoto, GG; Whitesides, J; Colvin, M; Safi, R; Chao, NJ; McDonnell, DP
Published in: Proc Natl Acad Sci U S A
August 1, 2006

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.

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Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 1, 2006

Volume

103

Issue

31

Start / End Page

11707 / 11712

Location

United States

Related Subject Headings

  • p-Aminoazobenzene
  • Transcription Factors
  • Signal Transduction
  • Retinoids
  • Retinal Dehydrogenase
  • Mice, SCID
  • Mice
  • Isoenzymes
  • Humans
  • Homeodomain Proteins
 

Citation

APA
Chicago
ICMJE
MLA
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Chute, J. P., Muramoto, G. G., Whitesides, J., Colvin, M., Safi, R., Chao, N. J., & McDonnell, D. P. (2006). Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A, 103(31), 11707–11712. https://doi.org/10.1073/pnas.0603806103
Chute, John P., Garrett G. Muramoto, John Whitesides, Michael Colvin, Rachid Safi, Nelson J. Chao, and Donald P. McDonnell. “Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.Proc Natl Acad Sci U S A 103, no. 31 (August 1, 2006): 11707–12. https://doi.org/10.1073/pnas.0603806103.
Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, et al. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11707–12.
Chute, John P., et al. “Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells.Proc Natl Acad Sci U S A, vol. 103, no. 31, Aug. 2006, pp. 11707–12. Pubmed, doi:10.1073/pnas.0603806103.
Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, McDonnell DP. Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A. 2006 Aug 1;103(31):11707–11712.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

August 1, 2006

Volume

103

Issue

31

Start / End Page

11707 / 11712

Location

United States

Related Subject Headings

  • p-Aminoazobenzene
  • Transcription Factors
  • Signal Transduction
  • Retinoids
  • Retinal Dehydrogenase
  • Mice, SCID
  • Mice
  • Isoenzymes
  • Humans
  • Homeodomain Proteins