Cycling G1 CD34⁺/CD38⁺ cells potentiate the motility and engraftment of quiescent G0 CD34⁺/CD38^-/low severe combined immunodeficiency repopulating cells

The mechanism of human stem cell expansion ex vivo is not fully understood. Furthermore, little is known about the mechanisms of human stem cell homing/repopulation and the role that differentiating progenitor cells may play in these processes. We report that 2- to 3-day in vitro cytokine stimulation of human cord blood CD34⁺-enriched cells induces the production of short-term repopulating, cycling G1 CD34⁺/CD38⁺ cells with increased matrix metalloproteinase (MMP)-9 secretion as well as increased migration capacity to the chemokine stromal cell-derived factor-1 (SDF-1) and homing to the bone marrow of irradiated nonobese diabetic severe/combined immunodeficiency (NOD/SCID) mice. These cycling G1 cells enhance SDF-1-mediated in vitro migration and in vivo homing of quiescent GO CD34⁺ cells, which is partially abrogated after inhibition of MMP-2/-9 activity. Moreover, the engraftment potential of quiescent GO SCID repopulating cells (SRCs) is also increased by the cycling G1 CD34⁺/CD38⁺ cells. This effect is significantly abrogated after incubation of cycling G1 cells with a neutralizing anti-CXCR4 antibody. Our data suggest synergistic interactions between accessory cycling G1 CD34⁺/CD38⁺ committed progenitor cells and quiescent, primitive G0 CD34⁺/CD38 ^-low SRC/stem cells, the former increasing the motility and engraftment potential of the latter, partly via secretion of MMP-9.