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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-02-0564.
Submitted February 21, 2002
Accepted June 5, 2002
Human CD34+CXCR4 - sorted cells harbor intracellular CXCR4, which can functionally be 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*
Immunology, Weizmann Institute of Science, Rehovot, Israel
Gene Therapy, Hadassah University Hospital, Jerusalem, Israel
Hematology Institute, Sourasky Medical Center, Tel Aviv, Israel
Oncological Sciences Dept., IRCC Cancer Inst., Division of Clinical Oncology, Candiolo, Italy
BMT, Chaim Sheba Medical Center, Tel Hashomer, Israel
* Corresponding author; email: Tsvee.Lapidot{at}weizmann.ac.il.
Homing and repopulation of NOD/SCID mice by enriched human CD34+ stem cells from cord blood, bone marrow, or mobilized PBL are dependent on SDF-1/CXCR4 interactions. Recently, human cord and fetal blood CD34+CD38-CXCR4- and CXCR4+ cells sorted with neutralizing anti CXCR4 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 non-sorted and SDF-1-migrated CD34+ cells. Co-injection 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 cytokine stimulation resulted in upregulation of both cell surface and intracellular CXCR4, restoring migration capacities towards 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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