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, Quentin I Churches, Simon A James, Songhui Li, Thalia Papayannopoulou, Susan K Nilsson
NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2016
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 ..View full abstract
The authors acknowledge Dani Cardozo and Jessica Hatwell-Humble for animal assistance and Andrea Reitsma and Cheang Be for technical assistance. We acknowledge Paul Savage, David Haylock, Shen Heazlewood, Ana Oteiza and Oliver Hutt for their intellectual input, figure design and assistance in the original synthesis of the compounds. We acknowledge Dean Sheppard for the provision of the alpha<INF>9</INF><SUP>flox/flox</SUP> mice, Warren Alexander for the provision of the vav-cre mice and Patrick Tam for the provision of RFP mice. We acknowledge Irene Volitakis for ICP-MS, Wioleta Kowalczyk for HPLC and FlowCore (Monash University) for flow cytometry services. This work was undertaken in part on the X-ray Fluorescence Microscopy beamline at the Australian Synchrotron, Victoria, Australia. This research was supported by the Science and Industry Endowment Fund, an ARC Future Fellowship and a CSIRO OCE Science Leader Fellowship to SKN and a CSIRO OCE post-doctoral fellowship to BC. The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government.