Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist
AuthorCao, B; Zhang, Z; Grassinger, J; Williams, B; Heazlewood, CK; Churches, QI; James, SA; Li, S; Papayannopoulou, T; Nilsson, SK
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
Florey Department of Neuroscience and Mental Health
Document TypeJournal Article
CitationsCao, 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 StatusOpen Access
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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