Glucocorticoid hormone-induced chromatin remodeling enhances human hematopoietic stem cell homing and engraftment

Abstract

Efficient hematopoietic stem cell (HSC) homing is important for hematopoietic cell transplantation (HCT), especially when HSC numbers are limited, as in the use of cord blood (CB). In a screen of small-molecule compounds, we identified glucocorticoid (GC) hormone signaling as an activator of CXCR4 expression in human CB HSCs and hematopoietic progenitor cells (HPCs). Short-term GC pretreatment of human CB HSCs and HPCs promoted SDF-1–CXCR4-axis-mediated chemotaxis, homing, and long-term engraftment when these cells were transplanted into primary- and secondary-recipient NSG mice. Mechanistically, activated glucocorticoid receptor binds directly to a glucocorticoid response element in the CXCR4 promoter and recruits the SRC-1–p300 complex to promote H4K5 and H4K16 histone acetylation, facilitating transcription of CXCR4. These results suggest a new and readily available means to enhance the clinical efficacy of CB HCT.

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Figure 1: Glucocorticoids increase cell surface expression of CXCR4 and promote chemotaxis mediated by the SDF-1–CXCR4 axis, homing, and long-term engraftment of human hematopoietic stem and progenitor cells.
Figure 2: Glucocorticoids enhance H4K5 and H4K16 acetylation associated with the CXCR4 promoter, facilitate expression of CXCR4, and promote homing of human CB CD34+ cells.

References

  1. 1

    Doulatov, S., Notta, F., Laurenti, E. & Dick, J.E. Cell Stem Cell 10, 120–136 (2012).

  2. 2

    Ballen, K.K., Gluckman, E. & Broxmeyer, H.E. Blood 122, 491–498 (2013).

  3. 3

    Fares, I. et al. Science 345, 1509–1512 (2014).

  4. 4

    Boitano, A.E. et al. Science 329, 1345–1348 (2010).

  5. 5

    Wagner, J.E. Jr. et al. Cell Stem Cell 18, 144–155 (2016).

  6. 6

    Morrison, S.J. & Scadden, D.T. Nature 505, 327–334 (2014).

  7. 7

    Peled, A. et al. Science 283, 845–848 (1999).

  8. 8

    Capitano, M.L. & Broxmeyer, H.E. Encyclopedia of Cell Biology 3, 624–631 (2016).

  9. 9

    Christopherson, K.W., II, Hangoc, G., Mantel, C.R. & Broxmeyer, H.E. Science 305, 1000–1003 (2004).

  10. 10

    Hoggatt, J., Singh, P., Sampath, J. & Pelus, L.M. Blood 113, 5444–5455 (2009).

  11. 11

    Chaurasia, P., Gajzer, D.C., Schaniel, C., D'Souza, S. & Hoffman, R. J. Clin. Invest. 124, 2378–2395 (2014).

  12. 12

    Gul, H. et al. Stem Cells Dev. 18, 831–838 (2009).

  13. 13

    Capitano, M.L., Hangoc, G., Cooper, S. & Broxmeyer, H.E. Stem Cells 33, 1975–1984 (2015).

  14. 14

    Högger, P. & Rohdewald, P. Steroids 59, 597–602 (1994).

  15. 15

    Broxmeyer, H.E. et al. J. Exp. Med. 201, 1307–1318 (2005).

  16. 16

    Kadmiel, M. & Cidlowski, J.A. Trends Pharmacol. Sci. 34, 518–530 (2013).

  17. 17

    Watson, L.C. et al. Nat. Struct. Mol. Biol. 20, 876–883 (2013).

  18. 18

    McKenna, N.J. & O'Malley, B.W. Cell 108, 465–474 (2002).

  19. 19

    Lonard, D.M. & O'malley, B.W. Mol. Cell 27, 691–700 (2007).

  20. 20

    Eberharter, A. & Becker, P.B. EMBO Rep. 3, 224–229 (2002).

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Acknowledgements

We thank other members in the Broxmeyer laboratory for helpful discussion and assistance and A.L. Sinn from the In vivo Therapeutics Core of the Indiana University School of Medicine for transplantation assistance. This work was supported by US Public Health Service Grants from the NIH to H.E.B. (R01 HL112669, R01 HL056416, U54 DK106846).

Author information

B.G. and H.E.B. conceived the research, designed and performed experiments, interpreted data, and wrote the manuscript. X.H. and S.C. performed intravenous injection and interpreted data.

Correspondence to Hal E Broxmeyer.

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Competing interests

H.E.B. is a member of the Medical Scientific Advisory Board of CordUse, a cord blood banking company based in Orlando, Florida.

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