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

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

Research output: Contribution to journalArticleResearchpeer-review

33 Citations (Scopus)

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 alpha9beta1/alpha4beta1 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 NODSCIDIL2Rgamma(-/-) 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 alpha9beta1/alpha4beta1 within the endosteal niche. These results support using dual alpha9beta1/alpha4beta1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.
Original languageEnglish
Article number11007
Number of pages13
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 15 Mar 2016

Cite this