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Blood, Vol. 93 No. 5 (March 1), 1999:
pp. 1524-1533
Enhanced Myeloid Progenitor Cell Cycling and Apoptosis in Mice
Lacking the Chemokine Receptor, CCR2
Suzanna Reid,
Alec Ritchie,
Landin Boring,
Jennifa Gosling,
Scott Cooper,
Giao Hangoc,
Israel F. Charo, and
Hal E. Broxmeyer
From the Departments of Microbiology/Immunology and Medicine, and The
Walther Oncology Center, Indiana University School of Medicine,
Indianapolis, IN; The Walther Cancer Institute, Indianapolis, IN; the
Cardiovascular Research Institute, Gladstone Institute of
Cardiovascular Disease, and the Department of Medicine, University of
California, San Francisco, CA.
Chemokines regulate hematopoiesis in part by influencing the
proliferative status of myeloid progenitor cells (MPC). Human MCP-1/murine JE, a myelosuppressive chemokine, specifically binds C-C
chemokine receptor 2 (CCR2). Transgenic mice containing a targeted
disruption in CCR2 that prevents expression of CCR2 mRNA and protein
and have MPC that are insensitive to inhibition by MCP-1 and JE in
vitro were assessed for potential abnormalities in growth of bone
marrow (BM) and spleen MPC. MPC in both unseparated and
c-kit+lin populations of BM from
CCR2-deficient ( /) mice were in a greatly increased proliferation
state compared with CCR2 littermate control (+/+) mice, an effect
not apparent with progenitors from spleens of CCR2 (/) mice.
Increased cycling status of CCR2 (/) BM MPC did not result in
increased numbers of nucleated cells or MPC in BM or spleens of CCR2
(/) mice. Possible reasons for this apparent discrepancy were
highlighted by flow cytometric analysis of
c-kit+lin BM cells and colony formation by
MPC subjected to delayed addition of growth factors. The
c-kit+lin population of BM cells from CCR2
(/) mice had a significantly higher percentage of apoptotic cells
than those from CCR2 (+/+) BM. However, elevated apoptosis was not
associated with decreased numbers of
c-kit+lin cells. The increased percentage
of apoptotic c-kit+lin cells was due to
elevated apoptosis within the c-kitdimlin,
but not the c-kitbrightlin, subpopulations
of cells. Consistent with enhanced apoptosis of phenotypically defined
cells, MPC from CCR2 (/) BM and purified c-kit+lin cells demonstrated decreased
cell survival in vitro upon delayed addition of growth factors. The
data suggest that signals received by CCR2 limit proliferation of
progenitor cells in the BM, but also enhance survival of these cells.
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