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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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 Date

  • March 31, 2010

Published In

Volume / Issue

  • 28 / 3

Start / End Page

  • 523 - 534

PubMed ID

  • 20054864

Pubmed Central ID

  • 20054864

Electronic International Standard Serial Number (EISSN)

  • 1549-4918

Digital Object Identifier (DOI)

  • 10.1002/stem.299

Language

  • eng

Conference Location

  • United States