Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells.
Fetal hematopoietic stem cells (HSCs) regenerate daughter HSCs in irradiated recipients more rapidly than do adult HSCs. However, both types of HSCs divide in vitro with the same cell-cycle transit times, suggesting different intrinsically determined self-renewal activities. To investigate the mechanism(s) underlying these differences, we compared fetal and adult HSC responses to Steel factor (SF) stimulation in vitro and in vivo. These experiments were undertaken with both wild-type cells and W(41)/W(41) cells, which have a functionally deficient c-kit kinase. In vitro, fetal HSC self-renewal divisions, like those of adult HSCs, were found to be strongly dependent on c-kit activation, but the fetal HSCs responded to much lower SF concentrations in spite of indistinguishable levels of c-kit expression. Fetal W(41)/W(41) HSCs also mimicked adult wild-type HSCs in showing the same reduced rate of amplification in irradiated adult hosts (relative to fetal wild-type HSCs). Assessment of various proliferation and signaling gene transcripts in fetal and adult HSCs self-renewing in vitro revealed a singular difference in Ink4c expression. We conclude that the ability of fetal HSCs to execute symmetric self-renewal divisions more efficiently than adult HSCs in vivo may be dependent on specific developmentally regulated signals that act downstream of the c-kit kinase.
Bowie
Michelle B
MB
Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, 675 West 10th Avenue, Vancouver, BC, Canada.
Kent
David G
DG
Copley
Michael R
MR
Eaves
Connie J
CJ
D000818:Animals; D049109:Cell Proliferation; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000378:metabolism; D053686:Fetal Stem Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism*; D013997:Time Factors
D050763:Cyclin-Dependent Kinase Inhibitor p18; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit