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Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

Author

Listed:
  • Benjamin Cao

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Regenerative Medicine Institute, Monash University)

  • Zhen Zhang

    (Biomedical Manufacturing, CSIRO Manufacturing)

  • Jochen Grassinger

    (University Hospital Regensberg)

  • Brenda Williams

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Regenerative Medicine Institute, Monash University)

  • Chad K. Heazlewood

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Regenerative Medicine Institute, Monash University)

  • Quentin I. Churches

    (Biomedical Manufacturing, CSIRO Manufacturing)

  • Simon A. James

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Synchrotron)

  • Songhui Li

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Regenerative Medicine Institute, Monash University)

  • Thalia Papayannopoulou

    (University of Washington Seattle)

  • Susan K. Nilsson

    (Biomedical Manufacturing, CSIRO Manufacturing
    Australian Regenerative Medicine Institute, Monash University)

Abstract

The inherent disadvantages of using granulocyte colony-stimulating factor (G-CSF) for hematopoietic stem cell (HSC) mobilization have driven efforts to identify alternate strategies based on single doses of small molecules. Here, we show targeting α9β1/α4β1 integrins with a single dose of a small molecule antagonist (BOP (N-(benzenesulfonyl)-L-prolyl-L-O-(1-pyrrolidinylcarbonyl)tyrosine)) rapidly mobilizes long-term multi-lineage reconstituting HSC. Synergistic engraftment augmentation is observed when BOP is co-administered with AMD3100. Impressively, HSC in equal volumes of peripheral blood (PB) mobilized with this combination effectively out-competes PB mobilized with G-CSF. The enhanced mobilization observed using BOP and AMD3100 is recapitulated in a humanized NODSCIDIL2Rγ−/− model, demonstrated by a significant increase in PB CD34+ cells. Using a related fluorescent analogue of BOP (R-BC154), we show that this class of antagonists preferentially bind human and mouse HSC and progenitors via endogenously primed/activated α9β1/α4β1 within the endosteal niche. These results support using dual α9β1/α4β1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.

Suggested Citation

  • Benjamin Cao & Zhen Zhang & Jochen Grassinger & Brenda Williams & Chad K. Heazlewood & Quentin I. Churches & Simon A. James & Songhui Li & Thalia Papayannopoulou & Susan K. Nilsson, 2016. "Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11007
    DOI: 10.1038/ncomms11007
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    Cited by:

    1. Shen Y. Heazlewood & Tanveer Ahmad & Benjamin Cao & Huimin Cao & Melanie Domingues & Xuan Sun & Chad K. Heazlewood & Songhui Li & Brenda Williams & Madeline Fulton & Jacinta F. White & Tom Nebl & Chri, 2023. "High ploidy large cytoplasmic megakaryocytes are hematopoietic stem cells regulators and essential for platelet production," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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