Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist.
Nat Commun
; 7: 11007, 2016 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-26975966
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 α9ß1/α4ß1 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 α9ß1/α4ß1 within the endosteal niche. These results support using dual α9ß1/α4ß1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Rodaminas
/
Sulfonas
/
Células Madre Hematopoyéticas
/
Integrinas
/
Movilización de Célula Madre Hematopoyética
/
Integrina alfa4beta1
/
Dipéptidos
/
Compuestos Heterocíclicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Australia