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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Aldehyde Dehydrogenase / antagonists & inhibitors*
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Aldehyde Dehydrogenase / genetics
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Aldehyde Dehydrogenase / metabolism
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Aldehyde Dehydrogenase 1 Family
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Animals
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Antineoplastic Agents / pharmacology
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Division / drug effects
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Cell Division / physiology
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Cell Proliferation / drug effects*
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Cells, Cultured
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Cytoprotection / drug effects
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Cytoprotection / physiology*
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Enzyme Inhibitors / pharmacology*
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Enzyme Inhibitors / therapeutic use
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / enzymology*
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Hematopoietic Stem Cells / radiation effects
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Humans
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Mice
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Mice, Congenic
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Mice, Inbred C57BL
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RNA, Small Interfering / genetics
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Radiation, Ionizing
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Retinal Dehydrogenase
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Stem Cell Transplantation / methods*
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Tretinoin / metabolism
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Tretinoin / pharmacology
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p-Aminoazobenzene / analogs & derivatives
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p-Aminoazobenzene / pharmacology
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p-Aminoazobenzene / therapeutic use
Substances
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Antineoplastic Agents
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Enzyme Inhibitors
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RNA, Small Interfering
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C.I. Solvent Yellow 56
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Tretinoin
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p-Aminoazobenzene
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Aldehyde Dehydrogenase 1 Family
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Aldehyde Dehydrogenase
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ALDH1A1 protein, mouse
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Retinal Dehydrogenase