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Blood, 2 July 2009, Vol. 114, No. 1, pp. 49-59.
Prepublished online as a Blood First Edition Paper on May 5, 2009; DOI 10.1182/blood-2009-01-197988.


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HEMATOPOIESIS AND STEM CELLS

Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with {alpha}9β1 and {alpha}4β1 integrins

Jochen Grassinger1, David N. Haylock1, Melonie J. Storan1, Gemma O. Haines1, Brenda Williams1, Genevieve A. Whitty1, Andrew R. Vinson1, Cheang Ly Be1, Songhui Li1, Esben S. Sørensen2, Patrick P.L. Tam3, David T. Denhardt4, Dean Sheppard5, Peter F. Choong6, and Susan K. Nilsson1,7

1 Australian Stem Cell Centre, Clayton, Australia, 2 Department of Molecular Biology, University of Aarhus, Aarhus C, Denmark; 3 Embryology Unit, Children's Medical Research Institute, University of Sydney, Westmead, Australia; 4 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, and affiliated with the Cancer Institute of New Jersey, Trenton; 5 University of California, San Francisco, Mission Bay; 6 Department of Orthopaedics and University of Melbourne Department of Surgery, St Vincent's Hospital Melbourne, Fitzroy, Australia; and 7 Department of Pathology, University of Melbourne, Parkville, Australia

Osteopontin (OPN), a multifunctional acidic glycoprotein, expressed by osteoblasts within the endosteal region of the bone marrow (BM) suppresses the proliferation of hemopoietic stem and progenitor cells and also regulates their lodgment within the BM after transplantation. Herein we demonstrate that OPN cleavage fragments are the most abundant forms of this protein within the BM. Studies aimed to determine how hemopoietic stem cells (HSCs) interact with OPN revealed for the first time that murine and human HSCs express {alpha}9β1 integrin. The N-terminal thrombin cleavage fragment of OPN through its binding to the {alpha}9β1 and {alpha}4β1 integrins plays a key role in the attraction, retention, regulation, and release of hemopoietic stem and progenitor cells to, in, and from their BM niche. Thrombin-cleaved OPN (trOPN) acts as a chemoattractant for stem and progenitor cells, mediating their migration in a manner that involves interaction with {alpha}9β1 and {alpha}4β1 integrins. In addition, in the absence of OPN, there is an increased number of white blood cells and, specifically, stem and progenitor cells in the peripheral circulation.


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E. C. Forsberg and S. Smith-Berdan
Parsing the niche code: the molecular mechanisms governing hematopoietic stem cell adhesion and differentiation
Haematologica, November 1, 2009; 94(11): 1477 - 1481.
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