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Changes in the Proliferative Activity of Human Hematopoietic Stem Cells in NOD/SCID Mice and Enhancement of Their Transplantability after In Vivo Treatment with Cell Cycle Inhibitors
2 Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
3 Department of Biochemistry and the Biomedical Research Centre, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
4 Department of Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
5 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC V5Z 1L3, Canada
Address correspondence to Dr. C. Eaves, Terry Fox Laboratory, 601 West 10th Ave., Vancouver, BC V5Z 1L3, Canada. Phone: 604-877-6070; Fax: 604-877-0712; E-mail: ceaves{at}bccancer.bc.ca
Human hematopoietic tissue contains rare stem cells with multilineage reconstituting ability demonstrable in receptive xenogeneic hosts. We now show that within 3 wk nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver cells regenerate near maximum levels of daughter human hematopoietic stem cells (HSCs) able to repopulate secondary NOD/SCID mice. At this time, most of the human HSCs (and other primitive progenitors) are actively proliferating as shown by their sensitivity to treatments that kill cycling cells selectively (e.g., exposure to high specific-activity [3H]thymidine in vitro or 5-fluorouracil in vivo). Interestingly, the proliferating human HSCs were rapidly forced into quiescence by in vivo administration of stromal-derived factor-1 (SDF-1) and this was accompanied by a marked increase in the numbers of human HSCs detectable. A similar result was obtained when transforming growth factor-ß was injected, consistent with a reversible change in HSCs engrafting potential linked to changes in their cell cycle status. By 12 wk after transplant, most of the human HSCs had already entered Go and treatment with SDF-1 had no effect on their engrafting activity. These findings point to the existence of novel mechanisms by which inhibitors of HSC cycling can regulate the engrafting ability of human HSCs executing self-renewal divisions in vivo.
Key Words: TGF-ß • SDF-1 • cell cycle • stem cells • engraftment
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