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The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation

Martin, S. K. and Fitter, S. and Dutta, A. K. and Matthews, M. P. and Walkley, C. R. and Hall, M. N. and Ruegg, M. A. and Gronthos, S. and Zannettino, A. C. W.. (2015) The differential roles of mTORC1 and mTORC2 in mesenchymal stem cell differentiation. Stem cells, Vol. 33, H. 4. pp. 1359-1365.

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Official URL: http://edoc.unibas.ch/dok/A6337741

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Abstract

Adipocytes (AdCs) and osteoblasts (OBs) are derived from mesenchymal stem cells (MSCs) and differentiation toward either lineage is both mutually exclusive and transcriptionally controlled. Recent studies implicate the mammalian target of rapamycin (mTOR) pathway as important in determining MSC fate, with inhibition of mTOR promoting OB differentiation and suppressing AdC differentiation. mTOR functions within two distinct multiprotein complexes, mTORC1 and mTORC2, each of which contains the unique adaptor protein, raptor or rictor, respectively. While compounds used to study mTOR signalling, such as rapamycin and related analogues, primarily inhibit mTORC1, prolonged exposure can also disrupt mTORC2 function, confounding interpretation of inhibitor studies. As a result, the relative contribution of mTORC1 and mTORC2 to MSC fate determination remains unclear. In this study, we generated primary mouse MSCs deficient in either Rptor (RapKO) or Rictor (RicKO) using the Cre/loxP system. Cre-mediated deletion of Rptor or Rictor resulted in impaired mTORC1 and mTORC2 signalling, respectively. Under lineage-inductive culture conditions, RapKO MSC displayed a reduced capacity to form lipid-laden AdCs and an increased capacity to form a mineralised matrix. In contrast, RicKO MSC displayed reduced osteogenic differentiation capacity and enhanced adipogenic differentiation potential. Taken together, our findings reveal distinct roles for mTORC1 and mTORC2 in lineage commitment of MSCs. This article is protected by copyright. All rights reserved.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Biochemistry (Hall)
UniBasel Contributors:Hall, Michael N.
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:AlphaMed Press
ISSN:1066-5099
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 May 2015 08:45
Deposited On:08 May 2015 08:45

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