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

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

Cao, Benjamin ; Zhang, Zhen ; Grassinger, Jochen ; Williams, Brenda ; Heazlewood, Chad K ; Churches, Qentin I ; James, Simon A ; Li, Songhui ; Papayannopoulou, Thalia ; Nilsson, Susan K. / Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. In: Nature Communications. 2016 ; Vol. 7.
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title = "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 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.",
author = "Benjamin Cao and Zhen Zhang and Jochen Grassinger and Brenda Williams and Heazlewood, {Chad K} and Churches, {Qentin I} and James, {Simon A} and Songhui Li and Thalia Papayannopoulou and Nilsson, {Susan K}",
year = "2016",
month = "3",
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journal = "Nature Communications",
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Cao, B, Zhang, Z, Grassinger, J, Williams, B, Heazlewood, CK, Churches, QI, James, SA, Li, S, Papayannopoulou, T & Nilsson, SK 2016, 'Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist' Nature Communications, vol. 7, 11007. https://doi.org/10.1038/ncomms11007

Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. / Cao, Benjamin; Zhang, Zhen; Grassinger, Jochen; Williams, Brenda; Heazlewood, Chad K; Churches, Qentin I; James, Simon A; Li, Songhui; Papayannopoulou, Thalia; Nilsson, Susan K.

In: Nature Communications, Vol. 7, 11007, 15.03.2016.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist

AU - Cao, Benjamin

AU - Zhang, Zhen

AU - Grassinger, Jochen

AU - Williams, Brenda

AU - Heazlewood, Chad K

AU - Churches, Qentin I

AU - James, Simon A

AU - Li, Songhui

AU - Papayannopoulou, Thalia

AU - Nilsson, Susan K

PY - 2016/3/15

Y1 - 2016/3/15

N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/26975966

U2 - 10.1038/ncomms11007

DO - 10.1038/ncomms11007

M3 - Article

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11007

ER -