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

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Cao, B; Zhang, Z; Grassinger, J; Williams, B; Heazlewood, CK; Churches, QI; James, SA; Li, S; Papayannopoulou, T; Nilsson, SKDate
2016-03-01Source Title
Nature CommunicationsPublisher
NATURE PUBLISHING GROUPAffiliation
Clinical PathologyFlorey Department of Neuroscience and Mental Health
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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 AccessAbstract
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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