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mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis

Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source of factors such as CXCL12 and IL-7 which are crucial for B-cell development. Recent studies from our laboratory and others have shown that deletion of Rptor, a unique component of the mTORC1 nutrient-sensing c...

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Autores principales: Martin, Sally K., Fitter, Stephen, El Khawanky, Nadia, Grose, Randall H., Walkley, Carl R., Purton, Louise E., Ruegg, Markus A., Hall, Michael N., Gronthos, Stan, Zannettino, Andrew C. W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162303/
https://www.ncbi.nlm.nih.gov/pubmed/30266921
http://dx.doi.org/10.1038/s41598-018-32858-5
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author Martin, Sally K.
Fitter, Stephen
El Khawanky, Nadia
Grose, Randall H.
Walkley, Carl R.
Purton, Louise E.
Ruegg, Markus A.
Hall, Michael N.
Gronthos, Stan
Zannettino, Andrew C. W.
author_facet Martin, Sally K.
Fitter, Stephen
El Khawanky, Nadia
Grose, Randall H.
Walkley, Carl R.
Purton, Louise E.
Ruegg, Markus A.
Hall, Michael N.
Gronthos, Stan
Zannettino, Andrew C. W.
author_sort Martin, Sally K.
collection PubMed
description Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source of factors such as CXCL12 and IL-7 which are crucial for B-cell development. Recent studies from our laboratory and others have shown that deletion of Rptor, a unique component of the mTORC1 nutrient-sensing complex, early in the osteoblast lineage development results in defective bone development in mice. In this study, we now demonstrate that mTORC1 signalling in pre-osteoblasts is required for normal B-lymphocyte development in mice. Targeted deletion of Rptor in osterix-expressing pre-osteoblasts (Rptor(ob)(−/−)) leads to a significant reduction in the number of B-cells in the bone marrow, peripheral blood and spleen at 4 and 12 weeks of age. Rptor(ob)(−/−) mice also exhibit a significant reduction in pre-B and immature B-cells in the BM, indicative of a block in B-cell development from the pro-B to pre-B cell stage. Circulating levels of IL-7 and CXCL12 are also significantly reduced in Rptor(ob)(−/−) mice. Importantly, whilst Rptor-deficient osteoblasts are unable to support HSC differentiation to B-cells in co-culture, this can be rescued by the addition of exogenous IL-7 and CXCL12. Collectively, these findings demonstrate that mTORC1 plays an important role in extrinsic osteoblastic regulation of B-cell development.
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spelling pubmed-61623032018-10-02 mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis Martin, Sally K. Fitter, Stephen El Khawanky, Nadia Grose, Randall H. Walkley, Carl R. Purton, Louise E. Ruegg, Markus A. Hall, Michael N. Gronthos, Stan Zannettino, Andrew C. W. Sci Rep Article Skeletal osteoblasts are important regulators of B-lymphopoiesis, serving as a rich source of factors such as CXCL12 and IL-7 which are crucial for B-cell development. Recent studies from our laboratory and others have shown that deletion of Rptor, a unique component of the mTORC1 nutrient-sensing complex, early in the osteoblast lineage development results in defective bone development in mice. In this study, we now demonstrate that mTORC1 signalling in pre-osteoblasts is required for normal B-lymphocyte development in mice. Targeted deletion of Rptor in osterix-expressing pre-osteoblasts (Rptor(ob)(−/−)) leads to a significant reduction in the number of B-cells in the bone marrow, peripheral blood and spleen at 4 and 12 weeks of age. Rptor(ob)(−/−) mice also exhibit a significant reduction in pre-B and immature B-cells in the BM, indicative of a block in B-cell development from the pro-B to pre-B cell stage. Circulating levels of IL-7 and CXCL12 are also significantly reduced in Rptor(ob)(−/−) mice. Importantly, whilst Rptor-deficient osteoblasts are unable to support HSC differentiation to B-cells in co-culture, this can be rescued by the addition of exogenous IL-7 and CXCL12. Collectively, these findings demonstrate that mTORC1 plays an important role in extrinsic osteoblastic regulation of B-cell development. Nature Publishing Group UK 2018-09-28 /pmc/articles/PMC6162303/ /pubmed/30266921 http://dx.doi.org/10.1038/s41598-018-32858-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Martin, Sally K.
Fitter, Stephen
El Khawanky, Nadia
Grose, Randall H.
Walkley, Carl R.
Purton, Louise E.
Ruegg, Markus A.
Hall, Michael N.
Gronthos, Stan
Zannettino, Andrew C. W.
mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title_full mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title_fullStr mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title_full_unstemmed mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title_short mTORC1 plays an important role in osteoblastic regulation of B-lymphopoiesis
title_sort mtorc1 plays an important role in osteoblastic regulation of b-lymphopoiesis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162303/
https://www.ncbi.nlm.nih.gov/pubmed/30266921
http://dx.doi.org/10.1038/s41598-018-32858-5
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