title: 4-Hydroxynonenal inhibits cell proliferation and alters differentiation pathways in human fetal liver hematopoietic stem cells.
abstract: During fetal development, the liver serves as the primary hematopoietic organ in which hematopoietic stem cells (HSC) comprise a large proportion of hepatic cell populations. Because HSC are capable of initiating long-term hematopoiesis, injury to these cells may have ramifications with regard to the etiology of blood-borne diseases. In the current study, we examined the effects of 4-hydroxynonenal (4-HNE), a mutagenic alpha,beta-unsaturated aldehyde that can be produced in utero, on HSC proliferation, differentiation, viability and apoptosis. Exposure of HSC to acute single doses of 4-HNE as low as 1 nM inhibited HSC proliferation. Because 4-HNE rapidly disappears from culture media, a multiple dosing regime was also employed to approximate short-term steady state 4-HNE concentrations relevant to physiological oxidative stress. 4-Hydroxynonenal steady state concentrations as low as 1 microM altered HSC differentiation pathways, but did not affect apoptosis or cause cell death. In contrast, exposure to steady state 5 microM 4-HNE elicited a loss in viability, and increased the rate of apoptosis in total HSC populations. Collectively, our data indicate that cellular levels of 4-HNE associated with a low level of oxidative stress cause a loss of proliferation and viability and alter differentiation pathways in human fetal HSC.
authors.affiliation: School of Public Health and Community Medicine, Department of Environmental and Occupational Health Sciences, 4225 Roosevelt Way NE Suite 100, University of Washington, Seattle, WA 98105-6099, USA.
authors.forename: Craig G
authors.initials: CG
authors.lastname: Moneypenny
authors.forename: Evan P
authors.initials: EP
authors.lastname: Gallagher
mesh_terms: D000447:Aldehydes / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000447:Aldehydes; C027576:4-hydroxy-2-nonenal