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.
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6 June 2005
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May 31 2005
Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size
Sebastian Stier,
Sebastian Stier
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Yon Ko,
Yon Ko
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Randolf Forkert,
Randolf Forkert
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Christoph Lutz,
Christoph Lutz
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Thomas Neuhaus,
Thomas Neuhaus
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Elisabeth Grünewald,
Elisabeth Grünewald
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
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Tao Cheng,
Tao Cheng
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
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David Dombkowski,
David Dombkowski
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
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Laura M. Calvi,
Laura M. Calvi
4Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642
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Susan R. Rittling,
Susan R. Rittling
5Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854
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David T. Scadden
David T. Scadden
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
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Sebastian Stier
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Yon Ko
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Randolf Forkert
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Christoph Lutz
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Thomas Neuhaus
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Elisabeth Grünewald
3Medizinische Poliklinik, University of Bonn, 53111 Bonn, Germany
Tao Cheng
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
David Dombkowski
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
Laura M. Calvi
4Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642
Susan R. Rittling
5Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854
David T. Scadden
1Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114
2Harvard Stem Cell Institute, Cambridge, MA 02138
CORRESPONDENCE David T. Scadden: [email protected] OR Yon Ko: [email protected]
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.
Received:
September 27 2004
Accepted:
April 13 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 201 (11): 1781–1791.
Article history
Received:
September 27 2004
Accepted:
April 13 2005
Citation
Sebastian Stier, Yon Ko, Randolf Forkert, Christoph Lutz, Thomas Neuhaus, Elisabeth Grünewald, Tao Cheng, David Dombkowski, Laura M. Calvi, Susan R. Rittling, David T. Scadden; Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size . J Exp Med 6 June 2005; 201 (11): 1781–1791. doi: https://doi.org/10.1084/jem.20041992
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