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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0564.
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Blood, 15 October 2002, Vol. 100, No. 8, pp. 2778-2786
HEMATOPOIESIS
Human CD34+CXCR4 sorted cells harbor
intracellular CXCR4, which can be functionally expressed and provide
NOD/SCID repopulation
Orit Kollet,
Isabelle Petit,
Joy Kahn,
Sarit Samira,
Ayelet Dar,
Amnon Peled,
Varda Deutsch,
Monica Gunetti,
Wanda Piacibello,
Arnon Nagler, and
Tsvee Lapidot
From the Immunology Department, Weizmann Institute of
Science, Rehovot, Israel; Gene Therapy Institute, Hadassah University
Hospital, Jerusalem, Israel; Hematology Institute, Tel Aviv Sourasky
Medical Center, Tel Aviv, Israel; Oncological Sciences Department,
Division of Clinical Oncology, Istituto per la Ricerca e la Cura del
Cancro (IRCC) Cancer Institute, Candiolo, Italy; and Bone Marrow
Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel.
Homing and repopulation of nonobese diabetic/severe combined
immunodeficient (NOD/SCID) mice by enriched human CD34+
stem cells from cord blood, bone marrow, or mobilized peripheral blood
are dependent on stromal cell-derived factor 1 (SDF-1)/CXCR4 interactions. Recently, human cord and fetal blood
CD34+CD38 CXCR4 and
CXCR4+ cells, sorted with neutralizing anti-CXCR4
monoclonal antibody (mAb), were shown to have similar NOD/SCID
repopulation potential. Herein we report that human cord blood
CD34+CXCR4+ (R4+) and
CD34+CXCR4 (R4) subsets, sorted
with neutralizing anti-CXCR4 mAb, engrafted NOD/SCID mice with
significantly lower levels of human cells compared with nonsorted and
SDF-1-migrated CD34+ cells. Coinjection of purified cells
with 10 µg anti-CXCR4 mAb significantly reduced engraftment of all
CD34+ subsets, and 50 µg completely abrogated engraftment
by R4 and CD34+ cells. Importantly,
R4 cells harbor intracellular CXCR4, which can be rapidly
induced to cell surface expression within a few hours. Moreover, 48 hours of cytokine stimulation resulted in up-regulation of both cell surface and intracellular CXCR4, restoring migration capacities toward
a gradient of SDF-1 and high-level NOD/SCID repopulation potential. In
addition, homing of sorted R4 cells into the murine bone
marrow and spleen was significantly slower and reduced compared to
CD34+ cells but yet CXCR4 dependent. In conclusion,
R4 cells express intracellular CXCR4, which can be
functionally expressed on the cell membrane to mediate SDF-1-dependent
homing and repopulation. Our results suggest dynamic CXCR4 expression on CD34+ stem and progenitor cells, regulating their
motility and repopulation capacities.
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