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

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

SUBMITTER: Cao B 

PROVIDER: S-EPMC4796355 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature