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Cycling G1 CD34⁺/CD38⁺ Cells Potentiate the Motility and Engraftment of Quiescent G0 CD34⁺/CD38^–/low Severe Combined Immunodeficiency Repopulating Cells

^a Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel;
^b Department of Obstetrics and Gynecology, Assaf-Harofeh Medical Center, Zerifin, Israel;
^c Gene Therapy Institute, Hadassah University Hospital, Jerusalem, Israel;
^d Oncological Sciences Department, Division of Clinical Oncology, IRCC Cancer Institute, Candiolo, Italy

Correspondence: Tsvee Lapidot, Ph.D., The Weizmann Institute of Science, Department of Immunology, P.O. Box 26, Rehovot, 76100, Israel. Telephone: 972-8-9342481; Fax: 972-8-9344141; e-mail: Tsvee.Lapidot{at}weizmann.ac.il

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 G0 CD34⁺ cells, which is partially abrogated after inhibition of MMP-2/-9 activity. Moreover, the engraftment potential of quiescent G0 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.

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