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Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization

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Abstract

G-CSF is the most often used agent in clinical hematopoietic stem and progenitor cell (HSPC) mobilization. However, in about 10 % of patients, G-CSF does not efficiently mobilize HSPC in clinically sufficient amounts. Cdc42 activity is involved in HSPC mobilization. In the present study, we explore the impact of Cdc42 inhibitor ML141 on G-CSF-mediated HSPC mobilization in mice. We found that the use of ML141 alone only triggered modest HSPC mobilization effect in mice. However, combination of G-CSF and ML141 significantly promoted HPSC counts and colony forming units in peripheral blood, as compared to mice treated with G-CSF alone. ML141 did not significantly alter the levels of SDF-1 and MMP-9 in the bone marrow, when used alone or in combination with G-CSF. We also found that G-CSF administration significantly increases the level of GTP-bound Cdc42, but does not alter the expression of Cdc42 in the bone marrow. Our data indicate that the Cdc42 signal is a negative regulator in G-CSF-mediated HSPC mobilization, and that inhibition of the Cdc42 signal efficiently improves mobilization efficiency. These findings may provide a new strategy for efficient HSPC mobilization, especially in patients with poor G-CSF response.

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References

  1. Motabi IH, DiPersio JF. Advances in stem cell mobilization. Blood Rev. 2012;26:267–78.

    Article  CAS  PubMed  Google Scholar 

  2. Bonig H, Papayannopoulou T. Hematopoietic stem cell mobilization: updated conceptual renditions. Leukemia. 2013;27:24–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Halter J, Kodera Y, Ispizua AU, et al. Severe events in donors after allogeneic hematopoietic stem cell donation. Haematologica. 2009;94:94–101.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Pulsipher MA, Chitphakdithai P, Miller JP, et al. Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113:3604–11.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Ryan MA, Nattamai KJ, Xing E, et al. Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization. Nat Med. 2010;16:1141–6.

    Article  CAS  PubMed  Google Scholar 

  6. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3:687–94.

    Article  CAS  PubMed  Google Scholar 

  7. Hoggatt J, Pelus LM. Mobilization of hematopoietic stem cells from the bone marrow niche to the blood compartment. Stem Cell Res Ther. 2011;2:13.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–37.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Hoggatt J, Pelus LM. Many mechanisms mediating mobilization: an alliterative review. Curr Opin Hematol. 2011;18:231–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Miki H, Takenawa T. Regulation of actin dynamics by WASP family proteins. J Biochem. 2003;134:309–13.

    Article  CAS  PubMed  Google Scholar 

  11. Brand AC, Morrison E, Milne S, Gonia S, Gale CA, Gow NA. Cdc42 GTPase dynamics control directional growth responses. Proc Natl Acad Sci USA. 2014;111:811–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Melendez J, Grogg M, Zheng Y. Signaling role of Cdc42 in regulating mammalian physiology. J Biol Chem. 2011;286:2375–81.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Florian MC, Dorr K, Niebel A, et al. Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation. Cell Stem Cell. 2012;10:520–30.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Geiger H, Zheng Y. Cdc42 and aging of hematopoietic stem cells. Curr Opin Hematol. 2013;20:295–300.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Chen C, Cao J, Song X, et al. Adrenaline administration promotes the efficiency of granulocyte colony stimulating factor-mediated hematopoietic stem and progenitor cell mobilization in mice. Int J Hematol. 2013;97:50–7.

    Article  CAS  PubMed  Google Scholar 

  16. Yang L, Zheng Y. Cdc42: a signal coordinator in hematopoietic stem cell maintenance. Cell Cycle. 2007;6:1445–50.

    Article  CAS  PubMed  Google Scholar 

  17. Xing Z, Ryan MA, Daria D, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108:2190–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Yang L, Wang L, Geiger H, Cancelas JA, Mo J, Zheng Y. Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc Natl Acad Sci USA. 2007;104:5091–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Fiorina P, Jurewicz M, Vergani A, et al. Targeting the CXCR4-CXCL12 axis mobilizes autologous hematopoietic stem cells and prolongs islet allograft survival via programmed death ligand 1. J Immunol. 2011;186:121–31.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Carion A, Benboubker L, Herault O, et al. Stromal-derived factor 1 and matrix metalloproteinase 9 levels in bone marrow and peripheral blood of patients mobilized by granulocyte colony-stimulating factor and chemotherapy. Relationship with mobilizing capacity of haematopoietic progenitor cells. Br J Haematol. 2003;122:918–26.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant 81000210,  81471580, 81200376, 81272206, 81270637 and 81370671) and Jiangsu Special Grant of Clinical Science (BL2012022 and BL2013010).

Conflict of interest

The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, No. 99, West Huaihai Road, Xuzhou, 221002, China

    Chong Chen, Xuguang Song, Sha Ma, Xue Wang, Huanxin Zhang, Qingyun Wu, Kai Zhao, Jiang Cao, Jianlin Qiao, Depeng Li, Lingyu Zeng, Zhengyu Li & Kailin Xu

  2. Laboratory of Transplantation and Immunology, Institute of Hematology, Xuzhou Medical College, Xuzhou, China

    Chong Chen, Jie Xu, Qingyun Wu, Kai Zhao, Jianlin Qiao, Xiaoshen Sun, Lingyu Zeng, Zhengyu Li & Kailin Xu

  3. Key Laboratory of Bone Marrow Stem Cell, Xuzhou Medical College, No. 84 West Huaihai Road, Xuzhou, 221002, Jiangsu Province, China

    Chong Chen, Xuguang Song, Sha Ma, Xue Wang, Qingyun Wu, Kai Zhao, Jiang Cao, Jianlin Qiao, Xiaoshen Sun, Zhengyu Li & Kailin Xu

  4. Department of Oncology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China

    Jie Xu

Authors
  1. Chong Chen
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  2. Xuguang Song
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  3. Sha Ma
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  4. Xue Wang
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  5. Jie Xu
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  6. Huanxin Zhang
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  7. Qingyun Wu
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  8. Kai Zhao
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  9. Jiang Cao
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  10. Jianlin Qiao
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  11. Xiaoshen Sun
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  12. Depeng Li
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  13. Lingyu Zeng
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  14. Zhengyu Li
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  15. Kailin Xu
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Corresponding authors

Correspondence to Lingyu Zeng or Kailin Xu.

Additional information

Chong Chen, Xuguang Song and Sha Ma contributed equally to this paper.

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Chen, C., Song, X., Ma, S. et al. Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization. Int J Hematol 101, 5–12 (2015). https://doi.org/10.1007/s12185-014-1690-z

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  • DOI: https://doi.org/10.1007/s12185-014-1690-z

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