Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size.
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.
Stier
Sebastian
S
Center for Regenerative Medicine and Technology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Ko
Yon
Y
Forkert
Randolf
R
Lutz
Christoph
C
Neuhaus
Thomas
T
Grünewald
Elisabeth
E
Cheng
Tao
T
Dombkowski
David
D
Calvi
Laura M
LM
Rittling
Susan R
SR
Scadden
David T
DT
D042683:Angiopoietin-1 / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001853:Bone Marrow / Q000502:physiology; D002135:Calcium-Binding Proteins; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D053495:Osteopontin; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D000072099:Serrate-Jagged Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D053495:Osteopontin