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Cell Biochemistry and Biophysics

, Volume 71, Issue 3, pp 1579–1587 | Cite as

Co-transplantation of Hematopoietic Stem Cells and Cxcr4 Gene-Transduced Mesenchymal Stem Cells Promotes Hematopoiesis

  • Wei Chen
  • Miao Li
  • Guizhen Su
  • Yu Zang
  • Zhiling Yan
  • Hai Cheng
  • Bin Pan
  • Jiang Cao
  • Qingyun Wu
  • Kai Zhao
  • Feng Zhu
  • Lingyu Zeng
  • Zhenyu Li
  • Kailin XuEmail author
Original Paper

Abstract

Mesenchymal stem cells (MSCs) are a promising candidate for cellular therapies. Co-transplantation of MSCs and hematopoietic stem cells (HSCs) promotes successful engraftment and improves hematopoietic recovery. In this study, the effects of co-transplantation of HSCs and mouse bone marrow (BM)-derived MSCs overexpressing CXCR4 (CXCR4-MSC) on CXCR4-MSC homing capacity and the reconstitution potential in lethally irradiated mice were evaluated. Recovery of donor-derived peripheral blood leukocytes and platelets was accelerated when CXCR4-MSCs were co-transplanted with BM cells. The frequency of c-kit+Sca+Lin HSCs was higher in recipient BM following co-transplantation of CXCR4-MSCs compared with the EGFP-MSC control and the BMT only groups. Surprisingly, the rate of early engraftment of donor-derived BM cells in recipients co-transplanted with CXCR4-MSCs was slightly lower than in the absence of MSCs on day 7. Moreover, co-transplantation of CXCR4-MSCs regulated the balance of T helper cells subsets. Hematopoietic tissue reconstitution was evaluated by histopathological analysis of BM and spleen. Co-transplantation of CXCR4-MSCs was shown to promote the recovery of hematopoietic organs. These findings indicate that co-transplantation of CXCR4-MSCs promotes the early phase of hematopoietic recovery and sustained hematopoiesis.

Keywords

Mesenchymal stem cell Bone marrow transplantation CXCR4 

Notes

Acknowledgments

The authors acknowledge CuiPing Zhang, GuoLiang Song, and Chong Chen for technical assistance. This manuscript was proofread by a native English professional with science background at Elixigen Corporation. This work was supported by grants from the National Natural Science Foundation of China (No. 81300441), Jiangsu province LiuDaRenCaiGaoFeng project (2013-WSN-080) and Xuzhou Science and Technology Project, China (No. XZZD1138).

References

  1. 1.
    Uccelli, A., Moretta, L., & Pistoia, V. (2008). Mesenchymal stem cells in health and disease. Nature Reviews Immunology, 8, 726–736.CrossRefPubMedGoogle Scholar
  2. 2.
    Tolar, J., Le Blanc, K., Keating, A., & Blazar, B. R. (2010). Concise review: Hitting the right spot with mesenchymal stromal cells. Stem Cells, 28, 1446–1455.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Nauta, A. J., & Fibbe, W. E. (2007). Immunomodulatory properties of mesenchymal stromal cells. Blood, 110, 3499–3506.CrossRefPubMedGoogle Scholar
  4. 4.
    Nombela-Arrieta, C., Ritz, J., & Silberstein, L. E. (2011). The elusive nature and function of mesenchymal stem cells. Nature Reviews Molecular Cell Biology, 12, 126–131.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Auletta, J. J., Cooke, K. R., Solchaga, L. A., Deans, R. J., & van’t Hof, W. (2010). Regenerative stromal cell therapy in allogeneic hematopoietic stem cell transplantation: Current impact and future directions. Biol Blood Marrow Transplant, 16, 891–906.PubMedCentralPubMedGoogle Scholar
  6. 6.
    Sordi, V. (2009). Mesenchymal stem cell homing capacity. Transplantation, 87, S42–S45.PubMedGoogle Scholar
  7. 7.
    Karp, J. M., & Leng Teo, G. S. (2009). Mesenchymal stem cell homing: The devil is in the details. Cell Stem Cell, 4, 206–216.CrossRefPubMedGoogle Scholar
  8. 8.
    Krampera, M. (2011). Mesenchymal stromal cell ‘licensing’: A multistep process. Leukemia, 25, 1408–1414.PubMedGoogle Scholar
  9. 9.
    Kahn, J., Byk, T., Jansson-Sjostrand, L., Petit, I., Shivtiel, S., Nagler, A., et al. (2004). Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation. Blood, 103, 2942–2949.CrossRefPubMedGoogle Scholar
  10. 10.
    Brenner, S., Whiting-Theobald, N., Kawai, T., Linton, G. F., Rudikoff, A. G., Choi, U., et al. (2004). CXCR4-transgene expression significantly improves marrow engraftment of cultured hematopoietic stem cells. Stem Cells, 22, 1128–1133.CrossRefPubMedGoogle Scholar
  11. 11.
    Wynn, R. F., Hart, C. A., Corradi-Perini, C., O’Neill, L., Evans, C. A., Wraith, J. E., et al. (2004). A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood, 104, 2643–2645.CrossRefPubMedGoogle Scholar
  12. 12.
    Rombouts, W. J., & Ploemacher, R. E. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17, 160–170.PubMedGoogle Scholar
  13. 13.
    Arthur, A., Rychkov, G., Shi, S., Koblar, S. A., & Gronthos, S. (2008). Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells, 26, 1787–1795.CrossRefPubMedGoogle Scholar
  14. 14.
    Cho, S. W., Sun, H. J., Yang, J. Y., Jung, J. Y., An, J. H., Cho, H. Y., et al. (2009). Transplantation of mesenchymal stem cells overexpressing RANK-Fc or CXCR4 prevents bone loss in ovariectomized mice. Molecular Therapy, 17, 1979–1987.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Zhang, D., Fan, G. C., Zhou, X., Zhao, T., Pasha, Z., Xu, M., et al. (2008). Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium. Journal of Molecular and Cellular Cardiology, 44, 281–292.CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Chen, W., Li, M., Li, Z., Yan, Z., Cheng, H., Pan, B., et al. (2012). CXCR4-transduced mesenchymal stem cells protect mice against graft-versus-host disease. Immunology Letters, 143(2), 161–169.CrossRefPubMedGoogle Scholar
  17. 17.
    Chen, W., Li, M., Cheng, H., Yan, Z., Cao, J., Pan, B., et al. (2013). Overexpression of the mesenchymal stem cell Cxcr4 gene in irradiated mice increases the homing capacity of these cells. Cell Biochemistry and Biophysics, 67(3), 1181–1191.CrossRefPubMedGoogle Scholar
  18. 18.
    Challen, G. A., Boles, N., Lin, K. K., & Goodell, M. A. (2009). Mouse hematopoietic stem cell identification and analysis. Cytometry A, 75, 14–24.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Peled, A., Petit, I., Kollet, O., Magid, M., Ponomaryov, T., Byk, T., et al. (1999). Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science, 283, 845–848.CrossRefPubMedGoogle Scholar
  20. 20.
    Sordi, V., Malosio, M. L., Marchesi, F., Mercalli, A., Melzi, R., Giordano, T., et al. (2005). Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood, 106, 419–427.CrossRefPubMedGoogle Scholar
  21. 21.
    Shi, M., Li, J., Liao, L., Chen, B., Li, B., Chen, L., et al. (2007). Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: Role in homing efficiency in NOD/SCID mice. Haematologica, 92, 897–904.CrossRefPubMedGoogle Scholar
  22. 22.
    Goodell, M. A., Rosenzweig, M., Kim, H., Marks, D. F., DeMaria, M., Paradis, G., et al. (1997). Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nature Medicine, 3, 1337–1345.CrossRefPubMedGoogle Scholar
  23. 23.
    Camargo, F. D., Chambers, S. M., Drew, E., McNagny, K. M., & Goodell, M. A. (2006). Hematopoietic stem cells do not engraft with absolute efficiencies. Blood, 107, 501–507.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Osawa, M., Hanada, K., Hamada, H., & Nakauchi, H. (1996). Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science, 273, 242–245.CrossRefPubMedGoogle Scholar
  25. 25.
    Waller, E. K., Ship, A. M., Mittelstaedt, S., Murray, T. W., Carter, R., Kakhniashvili, I., et al. (1999). Irradiated donor leukocytes promote engraftment of allogeneic bone marrow in major histocompatibility complex mismatched recipients without causing graft-versus-host disease. Blood, 94, 3222–3233.PubMedGoogle Scholar
  26. 26.
    Lu, X., Liu, T., Gu, L., Huang, C., Zhu, H., Meng, W., et al. (2009). Immunomodulatory effects of mesenchymal stem cells involved in favoring type 2 T cell subsets. Transplant Immunology, 22, 55–61.CrossRefPubMedGoogle Scholar
  27. 27.
    Eljaafari, A., Tartelin, M. L., Aissaoui, H., Chevrel, G., Osta, B., Lavocat, F., & Miossec, P. (2012). Bone marrow-derived and synovium-derived mesenchymal cells promote Th17 cell expansion and activation through caspase 1 activation: Contribution to the chronicity of rheumatoid arthritis. Arthritis and Rheumatism, 64, 2147–2157.PubMedGoogle Scholar
  28. 28.
    Li, F. R., Wang, X. G., Deng, C. Y., Qi, H., Ren, L. L., & Zhou, H. X. (2010). Immune modulation of co-transplantation mesenchymal stem cells with islet on T and dendritic cells. Clinical and Experimental Immunology, 161, 357–363.PubMedCentralPubMedGoogle Scholar
  29. 29.
    Ezquer, F., Ezquer, M., Contador, D., Ricca, M., Simon, V., & Conget, P. (2012). The antidiabetic effect of mesenchymal stem cells is unrelated to their transdifferentiation potential but to their capability to restore Th1/Th2 balance and to modify the pancreatic microenvironment. Stem Cells, 30, 1664–1674.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Wei Chen
    • 1
    • 3
    • 4
  • Miao Li
    • 2
  • Guizhen Su
    • 1
  • Yu Zang
    • 1
  • Zhiling Yan
    • 1
  • Hai Cheng
    • 1
  • Bin Pan
    • 1
  • Jiang Cao
    • 1
  • Qingyun Wu
    • 1
  • Kai Zhao
    • 1
  • Feng Zhu
    • 1
  • Lingyu Zeng
    • 1
  • Zhenyu Li
    • 1
  • Kailin Xu
    • 1
    • 3
    • 4
    Email author
  1. 1.Department of Hematologythe Affiliated Hospital of Xuzhou Medical CollegeXuzhouPeople’s Republic of China
  2. 2.Xuzhou Children’s HospitalXuzhouPeople’s Republic of China
  3. 3.Xuzhou Medical CollegeBlood Diseases InstituteXuzhouPeople’s Republic of China
  4. 4.Key Laboratory of Bone Marrow Stem CellXuzhouPeople’s Republic of China

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