Characterization of chemokine receptors expressed in primitive blood cellsduring human hematopoietic ontogeny

Chemokines are capable of regulating a variety of fundamental processes of hematopoietic cells that include proliferation, differentiation, and migrat ion, To evaluate potential chemokine signaling pathways important to the re gulation of primitive human hematopoietic cells, we examined chemokine rece ptor expression of highly purified subpopulations of uncommitted human bloo d cells. CXCR1-, CXCR2-, CXCR4-, and CCR5-expressing cells were detected by flow cytometry among human blood subsets depleted of lineage-restricted ce lls (Lin(-)) derived from adult bone marrow, mobilized peripheral blood, co rd blood (CB), and circulating fetal blood. Although these chemokine recept ors could be detected on Lin- cells throughout human development, only CXCR 4 could be detected in CD34(-)CD38(-)Lin(-) and CD34(+)CD38(-)Lin(-) subfra ctions enriched for stem cell function, suggesting that independent of onto geny, CXCR4-mediated signals are critical to primitive hematopoiesis, Disti nct to other stages of human hematopoietic development, primitive CB cells expressed higher levels of CXCR1, CXCR2, CCR5, and CXCR4 on both CD34(-)CD3 8(-)Lin(-) and CD34(+)CD38(-)Lin(-) subsets, Isolation of these fractions r evealed 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 resu lts, we suggest that signaling pathways mediated by chemokine receptors ide ntified here may play a fundamental role in hematopoietic stem cell regulat ion and provide alternative receptor targets for retroviral pseudotyping fo r genetic modification of repopulating cells.