Rapid and efficient homing of human CD34(+)CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice

Stem cell homing into the bone microenvironment is the first step in the in itiation of marrow-derived blood cells. It is reported that human severe co mbined immunodeficient (SCID) repopulating cells home and accumulate rapidl y, within a few hours, in the bone marrow and spleen of immunodeficient mic e previously conditioned with total body irradiation. Primitive CD34(+)CD38 (-/low)CXCR4(+) cells capable of engrafting primary and secondary recipient mice selectively homed to the bone marrow and spleen, whereas CD34(-)CD38( -/low)Lin(-) cells were not detected. Moreover, whereas freshly isolated CD 34(+)CD38(+/high) cells did not home, in vivo stimulation with granulocyte colony-stimulating factor as part of the mobilization process, or in vitro stem cell factor stimulation for 2 to 4 days, potentiated the homing capabi lities of cytokine-stimulated CD34(+)CD38(+) cells. Homing of enriched huma n CD34(+) cells was inhibited by pretreatment with anti-CXCR4 antibodies. M oreover, primitive CD34(+)CD38(-/low)CXCR4(+) cells also homed in response to a gradient of human stromal cell-derived factor 1 (SDF-1), directly inje cted into the bone marrow or spleen of nonirradiated NOD/SCID mice. Homing was also inhibited by pretreatment of CD34(+) cells with antibodies for the major integrins VLA-4, VLA-5, and LFA-1. Pertussis toxin, an inhibitor of signals mediated by G alpha (i) proteins, inhibited SDF-1-mediated in vitro transwell migration but not adhesion or in vivo homing of CD34(+) cells. H oming of human CD34(+) cells was also blocked by chelerythrine chloride, a broad-range protein kinase C inhibitor. This study reveals rapid and effici ent homing to the murine bone marrow by primitive human CD34(+)CD38(-/low)C XCR4(+) cells that is integrin mediated and depends on activation of the pr otein kinase C signal transduction pathway by SDF-1. (Blood. 2001;97: 3283- 3291) (C) 2001 by The American Society of Hematology.