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Kinetic evidence of the regeneration of multilineage hematopoiesis from
primitive cells in normal human bone marrow transplanted into
immunodeficient mice
JD Cashman, T Lapidot, JC Wang, M Doedens, LD Shultz, P Lansdorp, JE Dick and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Based on initial observations of human CD34+ Thy-1+ cells and long-term
culture-initiating cells (LTC-IC) in the bone marrow of some sublethally
irradiated severe combined immunodeficient (SCID) mice transplanted
intravenously with normal human marrow cells, and the subsequent finding
that the NOD/LtSz-scid/scid (NOD/SCID) mouse supports higher levels of
human cell engraftment, we undertook a series of time course experiments to
examine posttransplant changes in the number, tissue distribution, cycling
activity, and in vivo differentiation pattern of various human
hematopoietic progenitor cell populations in this latter mouse model. These
studies showed typical rapid posttransplant recovery curves for human CD34-
CD19+ (B-lineage) cells, CD34+ granulopoietic, erythroid, and multilineage
colony-forming cells (CFC), LTC-IC, and CD34+ Thy-1+ cells from a small
initial population representing <0.1% of the original transplant. The
most primitive human cell populations reached maximum values at 5 weeks
posttransplant, after which they declined. More mature cell types peaked
after another 5 weeks and then declined. A 2-week course of thrice weekly
injections of human Steel factor, interleukin (IL)-3,
granulocyte-macrophage colony-stimulating factor (GM-CSF), and
erythropoietin (administered just before the mice were killed for analysis)
did not alter the pace of regeneration of either primitive or mature human
hematopoietic cells, or their predominantly granulopoietic and B-lymphoid
pattern of differentiation, although a significant enhancing effect on the
level of human cell engraftment sustained after 3 months was noted. Cycling
studies showed the human CFC present at 4 to 5 weeks posttransplant to be
rapidly proliferating even in mice not given human growth factors. However,
by 10 weeks and thereafter, only quiescent human CFC were detected;
interestingly, even in mice that were given the 2-week course of growth
factor injections. These studies indicate the use of this model for future
analysis of the properties and in vivo regulation of primitive human
hematopoietic cells that possess in vivo repopulating ability.
Volume 89,
Issue 12,
pp. 4307-4316,
06/15/1997
Copyright © 1997 by The American Society of Hematology

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