Journal Article

Osteoblastic cells regulate the haematopoietic stem cell niche

Kronenberg, H. M., Martin, R. P., Bringhurst, F. R., Scadden, D. T., Milner, L. A., Knight, M. C., Weibrecht, K. W., Olson, D. P., Calvi, L. M., Adams, G. B., Schipani, E., Weber, J. M., Divieti, P.

2003

Overview

Stem cell fate is influenced by specialized microenvironments that remain poorly defined in mammals 1 , 2 , 3 . 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) 4 . 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 γ-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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Animals / Biological and medical sciences / Bone and Bones - cytology / Bone and Bones - metabolism / Bone marrow / Calcium-Binding Proteins / Cell Count / Cell Division - drug effects / Cell Survival - drug effects / Environment / Fundamental and applied biological sciences. Psychology / Hematopoietic Stem Cell Transplantation / Hematopoietic Stem Cells - cytology / Hematopoietic Stem Cells - drug effects / Hematopoietic Stem Cells - metabolism / Humanities and Social Sciences / Intercellular Signaling Peptides and Proteins / Jagged-1 Protein / letter / Ligands / Membrane Proteins - metabolism / Mice / Mice, Inbred C57BL / Mice, Transgenic / Microenvironments / multidisciplinary / Mutation - genetics / Osteoblasts - cytology / Osteoblasts - drug effects / Osteoblasts - metabolism / Osteopathic medicine / Parathyroid Hormone - pharmacology / Proteins - metabolism / Rats / Receptor, Parathyroid Hormone, Type 1 - metabolism / Receptors, Notch / Receptors, Parathyroid Hormone - metabolism / Science / Science (multidisciplinary) / Serrate-Jagged Proteins / Signal Transduction - drug effects / Stem cells / Stromal Cells - cytology / Stromal Cells - drug effects / Stromal Cells - metabolism / Vertebrates: blood, hematopoietic organs, reticuloendothelial system