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

By Benjamin Cao, Zhen Zhang, Jochen Grassinger, Brenda Williams, Chad K. Heazlewood, Quentin I. Churches, Simon A. James, Songhui Li, Thalia Papayannopoulou and Susan K. Nilsson

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 alpha(9)beta(1)/alpha(4)beta(1) 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 NODSCIDIL2R gamma (-/-) 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 alpha(9)beta(1)/alpha(4)beta(1) within the endosteal niche. These results support using dual alpha(9)beta(1)/alpha(4)beta(1) inhibitors as effective, rapid and transient mobilization agents with promising clinical applications

Topics: 610 Medizin, ddc:610
Publisher: 'Springer Science and Business Media LLC'
Year: 2016
DOI identifier: 10.1038/ncomms11007
OAI identifier: oai:epub.uni-regensburg.de:41845
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