4-Hydroxynonenal inhibits cell proliferation and alters differentiation pathways in human fetal liver hematopoietic stem cells.
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.
Moneypenny
Craig G
CG
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.
Gallagher
Evan P
EP
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
D000447:Aldehydes; C027576:4-hydroxy-2-nonenal