Cao, Benjamin and Zhang, Zhen and Grassinger, Jochen and Williams, Brenda and Heazlewood, Chad K. and Churches, Quentin I. and James, Simon A. and Li, Songhui and Papayannopoulou, Thalia and Nilsson, Susan K. (2016) Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. NATURE COMMUNICATIONS, 7: 11007. ISSN 2041-1723,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEMATOPOIETIC STEM-CELLS; COLONY-STIMULATING FACTOR; MULTIPLE ACTIVATION STATES; BONE-MARROW ENDOSTEUM; PLUS G-CSF; PROGENITOR CELLS; CXCR4 ANTAGONIST; MECHANISTIC DIFFERENCES; AUSTRALIAN SYNCHROTRON; BINDING-PROPERTIES; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Onkogenomik |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 Mar 2019 14:57 |
| Last Modified: | 11 Mar 2019 14:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/2322 |
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