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, Hal E. Broxmeyer

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Abstract

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 (-/-) IBM 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-kit(dim)lin-, but not the ckit(bright)lin- , 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.

Original languageEnglish (US)
Pages (from-to)1524-1533
Number of pages10
JournalBlood
Volume93
Issue number5
StatePublished - Mar 1 1999

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Reid, S., Ritchie, A., Boring, L., Gosling, J., Cooper, S., Hangoc, G., Charo, I. F., & Broxmeyer, H. E. (1999). Enhanced myeloid progenitor cell cycling and apoptosis in mice lacking the chemokine receptor, CCR2. Blood, 93(5), 1524-1533.