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 α9β1/α4β1 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 α9β1/α4β1 within the endosteal niche. These results support using dual α9β1/α4β1 inhibitors as effective, rapid and transient mobilization agents with promising clinical applications.
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: University Hospital Regensberg, Department of Hematology and Oncology, Franz-Josef-Strauß-Allee 11, Regensburg 93053, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grassinger
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Brenda
authors.initials: B
authors.lastname: Williams
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Chad K
authors.initials: CK
authors.lastname: Heazlewood
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.
authors.forename: Quentin I
authors.initials: QI
authors.lastname: Churches
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Synchrotron, Clayton, Victoria 3168, Australia.
authors.forename: Simon A
authors.initials: SA
authors.lastname: James
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Songhui
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Medicine/Hematology, University of Washington Seattle, 1705 NE Pacific, Box 357710, Seattle, Washington 98195-7710, USA.
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.affiliation: Biomedical Manufacturing, CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia.|Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Nilsson
mesh_terms: D000818:Animals; D001596:Benzylamines; D000080027:Cyclams; D004151:Dipeptides / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D012235:Rhodamines / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D004151:Dipeptides; D006571:Heterocyclic Compounds; C507942:Il2rg protein, mouse; D039041:Integrin alpha4beta1; D016023:Integrins; D053631:Interleukin Receptor Common gamma Subunit; C459088:N-(benzenesulfonyl)-prolyl-O-(1-pyrrolidinylcarbonyl)tyrosine; C000592477:R-BC154; D019718:Receptors, CXCR4; D012235:Rhodamines; D013450:Sulfones; C113256:integrin alpha 9 beta 1; C088327:plerixafor