4-Hydroxynonenal inhibits cell proliferation and alters differentiation pathways in human fetal liver hematopoietic stem cells

Biochem Pharmacol. 2005 Jan 1;69(1):105-12. doi: 10.1016/j.bcp.2004.09.001.

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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehydes / pharmacology*
  • Cell Differentiation / drug effects*
  • Cell Differentiation / physiology
  • Cell Proliferation / drug effects*
  • Cells, Cultured
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Liver / cytology
  • Liver / drug effects*
  • Liver / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology

Substances

  • Aldehydes
  • 4-hydroxy-2-nonenal