title: Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity.
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.
authors.affiliation: Division of Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Garrett G
authors.initials: GG
authors.lastname: Muramoto
authors.forename: J Lauren
authors.initials: JL
authors.lastname: Russell
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.forename: Alice B
authors.initials: AB
authors.lastname: Salter
authors.forename: Heather A
authors.initials: HA
authors.lastname: Himburg
authors.forename: Pamela
authors.initials: P
authors.lastname: Daher
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Meadows
authors.forename: Phuong
authors.initials: P
authors.lastname: Doan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Storms
authors.forename: Nelson J
authors.initials: NJ
authors.lastname: Chao
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: John P
authors.initials: JP
authors.lastname: Chute
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D006801:Humans; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics; D011839:Radiation, Ionizing; D050697:Retinal Dehydrogenase; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; C007368:C.I. Solvent Yellow 56; D014212:Tretinoin; D010128:p-Aminoazobenzene; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase