12 November 2020

The study of Bioenergetics of stem cell mechanoresponses, published in Biomaterials is carried out in a collaboration between Werner Koopman, theme Metabolic Diseases, and colleagues from the Radboud University and California Institute of Technology.

Cells respond to the mechanical properties of the extracellular matrix (ECM) through formation of focal adhesions (FAs), re-organization of the actin cytoskeleton and adjustment of cell contractility. These are energy-demanding processes, but a potential causality between mechanical cues (matrix stiffness) and cellular (energy) metabolism remains largely unexplored. Here, we cultured human mesenchymal stem cells (hMSCs) on stiff or soft substrate and demonstrate that cytoskeletal reorganization and FA formation spreading on stiff substrates lead to a drop in intracellular ATP levels, correlating with activation of AMP-activated protein kinase (AMPK) and a jump in energy production. The resulting increase in ATP levels further facilitates cell spreading and reinforces cell tension of the steady state. This feedback loop was not present on soft substrates, as the lack of ‘exercise’ during initial contact prevented the cell from activating energy production. Together, these findings reveal a hitherto unidentified relationship between energy expenditure and the cellular mechanoresponse, and point to AMPK as a key mediator of stem cell fate in response to ECM mechanics.

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