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

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    32
    Author
    Cao, B; Zhang, Z; Grassinger, J; Williams, B; Heazlewood, CK; Churches, QI; James, SA; Li, S; Papayannopoulou, T; Nilsson, SK
    Date
    2016-03-01
    Source Title
    Nature Communications
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    James, Simon; Nilsson, Susan
    Affiliation
    Clinical Pathology
    Florey Department of Neuroscience and Mental Health
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Cao, B., Zhang, Z., Grassinger, J., Williams, B., Heazlewood, C. K., Churches, Q. I., James, S. A., Li, S., Papayannopoulou, T. & Nilsson, S. K. (2016). Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. NATURE COMMUNICATIONS, 7 (1), https://doi.org/10.1038/ncomms11007.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/259207
    DOI
    10.1038/ncomms11007
    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.

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