Dependence of Human Stem Cell Engraftment and Repopulation of NOD/SCID Mice on CXCR4
10.1126/science.283.5403.845
Crossref journal-article
American Association for the Advancement of Science (AAAS)
Science (221)
Abstract

Stem cell homing and repopulation are not well understood. The chemokine stromal cell–derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34 + CD38 −/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34 + cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

Bibliography

Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., Nagler, A., Ben-Hur, H., Many, A., Shultz, L., Lider, O., Alon, R., Zipori, D., & Lapidot, T. (1999). Dependence of Human Stem Cell Engraftment and Repopulation of NOD/SCID Mice on CXCR4. Science, 283(5403), 845–848.

Authors 14
  1. Amnon Peled (first)
  2. Isabelle Petit (additional)
  3. Orit Kollet (additional)
  4. Michal Magid (additional)
  5. Tanya Ponomaryov (additional)
  6. Tamara Byk (additional)
  7. Arnon Nagler (additional)
  8. Herzl Ben-Hur (additional)
  9. Ariel Many (additional)
  10. Leonard Shultz (additional)
  11. Ofer Lider (additional)
  12. Ronen Alon (additional)
  13. Dov Zipori (additional)
  14. Tsvee Lapidot (additional)
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  23. Human cells were obtained after informed consent according to procedures approved by the Weizmann Committee. In all experiments samples of the same initial cell pool were compared. Differences in the results are due to the different CD34 + cell sources (cord blood bone marrow and mobilized peripheral blood). CD34 + enrichment flow cytometry and fluorescence-activated cell sorting (FACS) were performed as previously described (5 6). SDF-1 (125 ng/ml R&D Systems) transmigration assays were done as previously described (13) with 2 × 10 5 CD34 + cells. Percents in the results represent percent of initial 2 × 10 5 cells in the migrating and nonmigrating cell fractions. The sources for the reagents are as follows: PMA (100 ng/ml) was purchased from Sigma stem cell factor (SCF) and IL-6 (50 ng/ml) from R&D Systems and antibodies to CXCR4 from Pharmingen {12g5 monoclonal antibody [immunoglobulin G2a (IgG2a)]} or R&D Systems [MBA171 monoclonal antibody (IgG2a)] (10 μg per 2 × 10 5 cells). CXCR4 expression was always analyzed by double staining with anti-CD34. Polyclonal anti–SDF-1 (10 μg per mouse R&D Systems) was injected intravenously with the cells (2 × 10 5 cells per mouse) and 24 hours later injected again intraperitoneally. Control cells were incubated with anti-CD34 [IgG1 Becton Dickinson 10 μg per 2 × 10 5 cells]. Human lymphoid and myeloid cells were immunostained with anti-CD45 (Immuno Quality Products Groningen Netherlands) anti-CD19 and anti-CD56 (Coulter). Natural killer cells differentiated into mature CD56 + cells after incubation with human SCF (100 ng/ml) and human IL-15 (100 ng/ml R&D Systems) for 10 days. NOD/SCID and NOD/SCID β 2 -microglobulin knockout (20) mice were bred and maintained under defined flora in intraventilated cages and transplanted by injection into the tail vein after sublethal (375R) irradiation according to established protocols (5 6) approved by the Weizmann animal ethics committee. Southern (DNA) blot analysis with a human-specific α satellite probe and human-specific progenitor assays were done as previously described (5 6). Percent engraftment always indicates the percent of either human DNA or of human CD45 cells in the mouse bone marrow. The levels of engraftment were dependent on the injected cell dose the duration of the experiment and the source of human CD34 + cells. Cells were cultured either in serum-free media as previously described (6) or in media supplemented with 10% fetal calf serum.
  24. Supported by grants from the Israel Academy of Science and the Israel Cancer Research Fund (T.L.) the Germany MINERVA grant (A.P.) a grant from the Balfour Peisner Bone Marrow Cancer Research Fund (I.P) a grant from the Israel Ministry of Science (O.K.) and NIH grant A130389 (L.S.). We thank Y. Yarden E. Canaani M. Revel P. Lonai M. Feldman and A. B. David for critically reviewing this manuscript and J. Dick for NOD/SCID mice his pluripotent help and support and for critically reviewing the revised version of the manuscript.
Dates
Type When
Created 23 years, 1 month ago (July 27, 2002, 5:40 a.m.)
Deposited 1 year, 7 months ago (Jan. 12, 2024, 10:09 p.m.)
Indexed 4 days, 1 hour ago (Sept. 3, 2025, 7:02 a.m.)
Issued 26 years, 7 months ago (Feb. 5, 1999)
Published 26 years, 7 months ago (Feb. 5, 1999)
Published Print 26 years, 7 months ago (Feb. 5, 1999)
Funders 0

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@article{Peled_1999, title={Dependence of Human Stem Cell Engraftment and Repopulation of NOD/SCID Mice on CXCR4}, volume={283}, ISSN={1095-9203}, url={http://dx.doi.org/10.1126/science.283.5403.845}, DOI={10.1126/science.283.5403.845}, number={5403}, journal={Science}, publisher={American Association for the Advancement of Science (AAAS)}, author={Peled, Amnon and Petit, Isabelle and Kollet, Orit and Magid, Michal and Ponomaryov, Tanya and Byk, Tamara and Nagler, Arnon and Ben-Hur, Herzl and Many, Ariel and Shultz, Leonard and Lider, Ofer and Alon, Ronen and Zipori, Dov and Lapidot, Tsvee}, year={1999}, month=feb, pages={845–848} }