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Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3722-3729
Differentiation Stage-Specific Regulation of Primitive Human
Hematopoietic Progenitor Cycling by Exogenous and Endogenous Inhibitors
in an In Vivo Model
J.D. Cashman,
I. Clark-Lewis,
A.C. Eaves, and
C.J. Eaves
From the Terry Fox Laboratory, British Columbia Cancer Agency,
Biomedical Research Centre; and Departments of Medical Genetics,
Biochemistry and Molecular Biology, Medicine, and Pathology and
Laboratory Medicine, University of British Columbia, Vancouver, British
Columbia, Canada.
Nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice
transplanted with human cord blood or adult marrow cells and injected 6 weeks posttransplant with 2 daily doses of transforming growth
factor- 1 (TGF- 1), monocyte
chemoattractant protein-1 (MCP-1), or a nonaggregating form of
macrophage inflammatory protein-1 (MIP-1 ) showed unique patterns
of inhibition of human progenitor proliferation 1 day later.
TGF- 1 was active on long-term culture initiating cells
(LTC-IC) and on primitive erythroid and granulopoietic colony-forming
cells (HPP-CFC), but had no effect on mature CFC. MCP-1 inhibited the
cycling of both types of HPP-CFC but not LTC-IC. MIP-1 did not
inhibit either LTC-IC or granulopoietic HPP-CFC but was active on
erythroid HPP-CFC and mature granulopoietic CFC. All of these responses
were independent of the source of human cells transplanted. LTC-IC of
either human cord blood or adult marrow origin continue to proliferate
in NOD/SCID mice for many weeks, although the turnover of all types of
human CFC in mice transplanted with adult human marrow (but not cord
blood) is downregulated after 6 weeks. Interestingly, administration of
either MIP-1 , an antagonist of both MIP-1 and MCP-1 or
MCP-1(9-76), an antagonist of MCP-1 (and MCP-2 and MCP-3), into mice in
which human marrow-derived CFC had become quiescent, caused the rapid reactivation of these progenitors in vivo. These results provide the
first definition of stage-specific inhibitors of human hematopoietic progenitor cell cycling in vivo. In addition they show that endogenous chemokines can contribute to late graft failure, which can be reversed
by the administration of specific antagonists.

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