Lipid availability determines fate of skeletal progenitor cells via SOX9

Nick van Gastel, Steve Stegen, Guy Eelen, Sandra Schoors, Aurélie Carlier, Veerle W. Daniëls, Ninib Baryawno, Dariusz Przybylski, Maarten Depypere, Pieter-Jan Stiers, Dennis Lambrechts, Riet Van Looveren, Sophie Torrekens, Azeem Sharda, Patrizia Agostinis, Diether Lambrechts, Frederik Maes, Johan V. Swinnen, Liesbet Geris, Hans Van Oosterwyck, Bernard Thienpont, Peter Carmeliet, David T. Scadden and Geert Carmeliet ()
Additional contact information
Nick van Gastel: KU Leuven
Steve Stegen: KU Leuven
Guy Eelen: KU Leuven
Sandra Schoors: KU Leuven
Aurélie Carlier: KU Leuven
Veerle W. Daniëls: KU Leuven
Ninib Baryawno: Harvard University
Dariusz Przybylski: Brandeis University
Maarten Depypere: KU Leuven
Pieter-Jan Stiers: KU Leuven
Dennis Lambrechts: KU Leuven
Riet Van Looveren: KU Leuven
Sophie Torrekens: KU Leuven
Azeem Sharda: Harvard University
Patrizia Agostinis: KU Leuven
Diether Lambrechts: KU Leuven
Frederik Maes: KU Leuven
Johan V. Swinnen: KU Leuven
Liesbet Geris: KU Leuven
Hans Van Oosterwyck: KU Leuven
Bernard Thienpont: KU Leuven
Peter Carmeliet: KU Leuven
David T. Scadden: Harvard University
Geert Carmeliet: KU Leuven

Nature, 2020, vol. 579, issue 7797, 111-117

Abstract: Abstract The avascular nature of cartilage makes it a unique tissue1–4, 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.

Date: 2020
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DOI: 10.1038/s41586-020-2050-1

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