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Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.

Publication ,  Journal Article
Muramoto, GG; Russell, JL; Safi, R; Salter, AB; Himburg, HA; Daher, P; Meadows, SK; Doan, P; Storms, RW; Chao, NJ; McDonnell, DP; Chute, JP
Published in: Stem Cells
March 31, 2010

Hematopoietic stem cells (HSCs) are enriched for aldehyde dehydrogenase (ALDH) activity and ALDH is a selectable marker for human HSCs. However, the function of ALDH in HSC biology is not well understood. We sought to determine the function of ALDH in regulating HSC fate. Pharmacologic inhibition of ALDH with diethylaminobenzaldehyde (DEAB) impeded the differentiation of murine CD34(-)c-kit(+)Sca-1(+)lineage(-) (34(-)KSL) HSCs in culture and facilitated a ninefold expansion of cells capable of radioprotecting lethally irradiated mice compared to input 34(-)KSL cells. Treatment of bone marrow (BM) 34(-)KSL cells with DEAB caused a fourfold increase in 4-week competitive repopulating units, verifying the amplification of short-term HSCs (ST-HSCs) in response to ALDH inhibition. Targeted siRNA of ALDH1a1 in BM HSCs caused a comparable expansion of radioprotective progenitor cells in culture compared to DEAB treatment, confirming that ALDH1a1 was the target of DEAB inhibition. The addition of all trans retinoic acid blocked DEAB-mediated expansion of ST-HSCs in culture, suggesting that ALDH1a1 regulates HSC differentiation via augmentation of retinoid signaling. Pharmacologic inhibition of ALDH has therapeutic potential as a means to amplify ST-HSCs for transplantation purposes.

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Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

March 31, 2010

Volume

28

Issue

3

Start / End Page

523 / 534

Location

England

Related Subject Headings

  • p-Aminoazobenzene
  • Tretinoin
  • Stem Cell Transplantation
  • Signal Transduction
  • Retinal Dehydrogenase
  • Radiation, Ionizing
  • RNA, Small Interfering
  • Mice, Inbred C57BL
  • Mice, Congenic
  • Mice
 

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Muramoto, G. G., Russell, J. L., Safi, R., Salter, A. B., Himburg, H. A., Daher, P., … Chute, J. P. (2010). Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells, 28(3), 523–534. https://doi.org/10.1002/stem.299
Muramoto, Garrett G., J Lauren Russell, Rachid Safi, Alice B. Salter, Heather A. Himburg, Pamela Daher, Sarah K. Meadows, et al. “Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.Stem Cells 28, no. 3 (March 31, 2010): 523–34. https://doi.org/10.1002/stem.299.
Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P, et al. Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells. 2010 Mar 31;28(3):523–34.
Muramoto, Garrett G., et al. “Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.Stem Cells, vol. 28, no. 3, Mar. 2010, pp. 523–34. Pubmed, doi:10.1002/stem.299.
Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P, Meadows SK, Doan P, Storms RW, Chao NJ, McDonnell DP, Chute JP. Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells. 2010 Mar 31;28(3):523–534.
Journal cover image

Published In

Stem Cells

DOI

EISSN

1549-4918

Publication Date

March 31, 2010

Volume

28

Issue

3

Start / End Page

523 / 534

Location

England

Related Subject Headings

  • p-Aminoazobenzene
  • Tretinoin
  • Stem Cell Transplantation
  • Signal Transduction
  • Retinal Dehydrogenase
  • Radiation, Ionizing
  • RNA, Small Interfering
  • Mice, Inbred C57BL
  • Mice, Congenic
  • Mice