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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3722-3729.
Prepublished online as a Blood First Edition Paper on August 3, 2006; DOI 10.1182/blood-2006-04-014399.


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HEMATOPOIESIS

CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes

Antonia Wimmer, Sophia K. Khaldoyanidi, Martin Judex, Naira Serobyan, Richard G. DiScipio, and Ingrid U. Schraufstatter

From the Division of Cancer Biology, La Jolla Institute for Molecular Medicine, San Diego, CA; the Division of Vascular Biology, La Jolla Institute for Molecular Biology, San Diego, CA; and the Molecular Biology Program, Sidney Kimmel Cancer Center, La Jolla, CA.

Chemokines play a role in regulating hematopoietic stem cell function, including migration, proliferation, and retention. We investigated the involvement of CCL18 in the regulation of bone marrow hematopoiesis. Treatment of human long-term bone marrow cultures (LTBMCs) with CCL18 resulted in significant stimulation of hematopoiesis, as measured by the total number of hematopoietic cells and their committed progenitors produced in culture. Monocytes/macrophages, whose survival was almost doubled in the presence of CCL18 compared with controls, were the primary cells mediating this effect. Conditioned media from CCL18-treated mature monocytes fostered colony-promoting activity that increased the number of colonies formed by hematopoietic progenitor cells. Gene expression profiling of CCL18-stimulated monocytes demonstrated more than 200 differentially expressed genes, including those regulating apoptosis (caspase-8) and proliferation (IL-6, IL-15, stem cell factor [SCF]). Up-regulation of these cytokines was confirmed on the protein expression level. The contribution of SCF and IL-6 in CCL18-mediated stimulatory activity for hematopoiesis was confirmed by SCF- and IL-6–blocking antibodies that significantly inhibited the colony-promoting activity of CCL18-stimulated conditioned medium. In addition to the effect on monocytes, CCL18 facilitated the formation of the adherent layer in LTBMCs and increased the proliferation of stromal fibroblast-like cells.


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