Osteoblastic cells regulate the haematopoietic stem cell niche.
Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals. To explore the possibility that haematopoietic stem cells derive regulatory information from bone, accounting for the localization of haematopoiesis in bone marrow, we assessed mice that were genetically altered to produce osteoblast-specific, activated PTH/PTHrP receptors (PPRs). Here we show that PPR-stimulated osteoblastic cells that are increased in number produce high levels of the Notch ligand jagged 1 and support an increase in the number of haematopoietic stem cells with evidence of Notch1 activation in vivo. Furthermore, ligand-dependent activation of PPR with parathyroid hormone (PTH) increased the number of osteoblasts in stromal cultures, and augmented ex vivo primitive haematopoietic cell growth that was abrogated by gamma-secretase inhibition of Notch activation. An increase in the number of stem cells was observed in wild-type animals after PTH injection, and survival after bone marrow transplantation was markedly improved. Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.
Endocrine Unit, Department of Medicine, Center for Human Genetics and Molecular Pediatric Disease, University of Rochester School of Medicine, Rochester, New York 14642, USA.
L M
LM
Calvi
G B
GB
Adams
K W
KW
Weibrecht
J M
JM
Weber
D P
DP
Olson
M C
MC
Knight
R P
RP
Martin
E
E
Schipani
P
P
Divieti
F R
FR
Bringhurst
L A
LA
Milner
H M
HM
Kronenberg
D T
DT
Scadden
D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004777:Environment; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D051381:Rats; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D051880:Receptors, Notch; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C000606275:Jag1 protein, rat; D000072100:Jagged-1 Protein; D008024:Ligands; D008565:Membrane Proteins; D010281:Parathyroid Hormone; D011506:Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D051880:Receptors, Notch; D018016:Receptors, Parathyroid Hormone; D000072099:Serrate-Jagged Proteins