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Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells 2010 Mar 31;28(3):523-34

Date

01/08/2010

Pubmed ID

20054864

Pubmed Central ID

PMC3909217

DOI

10.1002/stem.299

Scopus ID

2-s2.0-77950589175   54 Citations

Abstract

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.

Author List

Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P, Meadows SK, Doan P, Storms RW, Chao NJ, McDonnell DP, Chute JP

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Aldehyde Dehydrogenase
Animals
Antineoplastic Agents
Cell Differentiation
Cell Division
Cell Proliferation
Cells, Cultured
Cytoprotection
Enzyme Inhibitors
Hematopoietic Stem Cells
Humans
Mice
Mice, Congenic
Mice, Inbred C57BL
RNA, Small Interfering
Radiation, Ionizing
Retinal Dehydrogenase
Signal Transduction
Stem Cell Transplantation
Tretinoin
p-Aminoazobenzene