@article{58ded0aa9d324ae48d44f500e698a044,
title = "Lipid availability determines fate of skeletal progenitor cells via SOX9",
abstract = "The avascular nature of cartilage makes it a unique tissue 1–4, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.",
keywords = "ANGIOGENESIS, AUTOPHAGY, BONE-MARROW, CARTILAGE, DIFFERENTIATION, GENE-EXPRESSION, GROWTH, IDENTIFICATION, MOUSE, STEM-CELL, Growth, Identification, Autophagy, Stem-cell, Cartilage, Angiogenesis, Bone-marrow, Mouse, Differentiation, Gene-expression",
author = "{van Gastel}, Nick and Steve Stegen and Guy Eelen and Sandra Schoors and Aurelie Carlier and Daniels, {Veerle W.} and Ninib Baryawno and Dariusz Przybylski and Maarten Depypere and Pieter-Jan Stiers and Dennis Lambrechts and {Van Looveren}, Riet and Sophie Torrekens and Azeem Sharda and Patrizia Agostinis and Diether Lambrechts and Frederik Maes and Johan Swinnen and Liesbet Geris and {Van Oosterwyck}, Hans and Bernard Thienpont and Peter Carmeliet and Scadden, {David T.} and Geert Carmeliet",
note = "Funding Information: Acknowledgements We thank K. Moermans, I. Stockmans, C. MacGillivray and H. Soled for technical assistance, A. Nagy for the CAG-eGFP mice, S. Murakami for the Col1a1-cre/ERT2 and DsRed mice, T. Yoshimori for the RFP-GFP-LC3 plasmid, R. A. Weinberg for the pLKO.1-sh-mSOX9-5 lentiviral plasmid, M. Mazzone for hypoxic glove box use, the histology core of the Harvard Department of Stem Cell and Regenerative Biology for histology services, the FACS cores of the KU Leuven and the Harvard Department of Stem Cell and Regenerative Biology for access to the flow cytometers, and the Cell Imaging Core and the Molecular Imaging and Photonics division of the KU Leuven and the Harvard Center for Biological Imaging for access to the confocal microscopes. This work was supported by grants from the Research Fund Flanders (FWO; G096414, G0A4216N and G0B3418N to G.C.), KUL grant C24/17/07 (G.C.), grants from the European Research Council (ERC 308223 to H.V.O., ERC 279100 to L.G. and ERC 269073 to P.C.), and long-term structural Methusalem funding by the Flemish Government (P.C.). N.v.G. is funded by BOF-KU Leuven GOA project 3M120209. P.J.S. is a fellow from the Agency for Innovation by Science and Technology in Flanders (IWT). S. Stegen, A.C. and Dennis L. are postdoctoral fellows of the FWO. V.W.D. is a fellow of the FWO and the Flemish League against Cancer (VLK). This work is part of Prometheus, the KU Leuven R&D Division of Skeletal Tissue Engineering. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = mar,
day = "5",
doi = "10.1038/s41586-020-2050-1",
language = "English",
volume = "579",
pages = "111--117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7797",
}