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Characterization of Chemokine Receptors Expressed in Primitive Blood Cells During Human Hematopoietic Ontogeny

^a The John P. Robarts Research Institute, Developmental Stem Cell Biology, London, Ontario; Department of Microbiology and Immunology, University of Western Ontario, London, Ontario;
^b London Health Sciences, Department of Medicine, London, Ontario;
^c Henderson Hospital, Hamilton, Ontario;
^d St. Joseph's Hospital, London, Ontario

Key Words. Chemokine receptors • Retroviral receptors • Human hematopoietic stem cells • Ontogeny

Mickie Bhatia, M.D., The John P. Robarts Research Institute, Developmental Stem Cell Biology, 100 Perth Drive, London, Ontario, N6A 5K8, Canada, and Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, Canada. Telephone: 519-663-5777, ext. 34166; Fax: 519-663-3789; e-mail: mbhatia{at}rri.on.ca

Chemokines are capable of regulating a variety of fundamental processes of hematopoietic cells that include proliferation, differentiation, and migration. To evaluate potential chemokine signaling pathways important to the regulation of primitive human hematopoietic cells, we examined chemokine receptor expression of highly purified subpopulations of uncommitted human blood cells. CXCR1-, CXCR2-, CXCR4-, and CCR5-expressing cells were detected by flow cytometry among human blood subsets depleted of lineage-restricted cells (Lin^–) derived from adult bone marrow, mobilized peripheral blood, cord blood (CB), and circulating fetal blood. Although these chemokine receptors could be detected on Lin^– cells throughout human development, only CXCR4 could be detected in CD34^–CD38^–Lin^– and CD34⁺CD38^–Lin^– subfractions enriched for stem cell function, suggesting that independent of ontogeny, CXCR4-mediated signals are critical to primitive hematopoiesis. Distinct to other stages of human hematopoietic development, primitive CB cells expressed higher levels of CXCR1, CXCR2, CCR5, and CXCR4 on both CD34^–CD38^–Lin^– and CD34⁺CD38^–Lin^– subsets. Isolation of these fractions revealed expression of additional chemokine receptors CCR7, CCR8, and Bonzo (STRL133), whereas BOB (GPR15) could not be detected. Our study illustrates that rare uncommitted hematopoietic cells express chemokine receptors not previously associated with primitive human blood cells. Based on these results, we suggest that signaling pathways mediated by chemokine receptors identified here may play a fundamental role in hematopoietic stem cell regulation and provide alternative receptor targets for retroviral pseudotyping for genetic modification of repopulating cells.

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