The Journal of Experimental Medicine
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Published online 31 May 2005 doi:10.1084/jem.20041992
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 11, 1781-1791
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ARTICLE

 Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size

Sebastian Stier1,2,3, Yon Ko3, Randolf Forkert1,2,3, Christoph Lutz1,2,3, Thomas Neuhaus3, Elisabeth Grünewald3, Tao Cheng1,2, David Dombkowski1,2, Laura M. Calvi4, Susan R. Rittling5, and David T. Scadden1,2

1 Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2 Harvard Stem Cell Institute, Cambridge, MA 02138
3 Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
4 Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642
5 Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854

CORRESPONDENCE David T. Scadden: scadden.david{at}mgh.harvard.edu OR Yon Ko: y.ko{at}jk-bonn.de

Stem cells reside in a specialized niche that regulates their abundance and fate. Components of the niche have generally been defined in terms of cells and signaling pathways. We define a role for a matrix glycoprotein, osteopontin (OPN), as a constraining factor on hematopoietic stem cells within the bone marrow microenvironment. Osteoblasts that participate in the niche produce varying amounts of OPN in response to stimulation. Using studies that combine OPN-deficient mice and exogenous OPN, we demonstrate that OPN modifies primitive hematopoietic cell number and function in a stem cell–nonautonomous manner. The OPN-null microenvironment was sufficient to increase the number of stem cells associated with increased stromal Jagged1 and Angiopoietin-1 expression and reduced primitive hematopoietic cell apoptosis. The activation of the stem cell microenvironment with parathyroid hormone induced a superphysiologic increase in stem cells in the absence of OPN. Therefore, OPN is a negative regulatory element of the stem cell niche that limits the size of the stem cell pool and may provide a mechanism for restricting excess stem cell expansion under conditions of niche stimulation.

Abbreviations used: CFC, colony-forming cell; CRA, competitive repopulation assay; IC, initiating cell; LTC, long-term culture; OPN, osteopontin; PTH, parathyroid hormone; SCF, stem cell factor.


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