Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP

Abstract

ach tissue has a specific composition of its extracellular matrix (ECM), which is associated with distinctive physical and mechanical properties. These mechanical properties are important for tissue structure, but also control cell function in physiology and disease 1,2. Cells sense the mechanical properties of the ECM through integrin receptors, and measure them by adjusting the contractility of their F-actin cytoskeleton: contractility is maximal when cells are free to spread on stiff ECM substrata, while it is progressively decreased on a soft ECM or in conditions of limited spreading 1. This is sufficient to control the switch between proliferation, differentiation and death in very diverse cell types, by regulating intracellular signalling pathways such as YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif, also known as WWTR1) 3,4 and SRF (serum response factor) 5,6. In support of this model, inhibition of key players that maintain F-actin contractility including the small GTPase RHO, ROCK (RHO kinase), MLCK (myosin light chain kinase) and non-muscle myosin (NMII) induce similar responses to a soft ECM 1. Yet, which other general aspects of cell biology are regulated by mechanical cues, and through which mechanism(s), remain largely unexplored. This is especially true in the case of metabolism, a fundamental engine that is constantly remodelled to match the energetic and biosynthetic requirements of the cell, whose connections to mechanical cues are only starting to emerge 7,8. Results Actomyosin regulates lipid metabolism. To test in an unbiased manner the possibility that actomyosin contractility regulates metabolism we used global metabolomics to compare cells in conditions of high contractility (plated on plastics) with cells in conditions of low contractility, by inhibiting ROCK and MLCK. Analysis of steady-state levels of multiple metabolites indicated clear differences between controls and treated cells (Fig. 1a and Supplementary

Lipid‐dependent coupling of secretory cargo sorting and trafficking at the trans‐Golgi network

“…Considering the important role of Arf1 in secretory cargo trafficking through the recruitment of effector proteins such as golgins, PKD, and FAPP2 , loss of adhesion‐mediated regulation of the Golgi and, particularly, the TGN is expected to affect Golgi‐dependent secretory cargo sorting and trafficking. Romani and co‐workers went one‐step further and established the Golgi complex itself as a mechanosensor organelle . They show that the Golgi complex responds to intracellular and extracellular mechanical forces such as actomyosin contractility and matrix stiffness, respectively, through alterations in DAG levels.…”

“…Inhibition of lipin‐1 by placing cells in a soft matrix sharply decreased DAG levels proving that lipin‐1 activity is sensitive toward actomyosin contractility. As a result, Arf1 levels at Golgi membranes dropped . This suggest that local changes in PA and DAG could impinge on Arf1 function.…”

Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP signaling pathway in the remodeling of blood vessels

“…Recent studies have shown that ECM mechanical cues mediate cell proliferation, differentiation, autophagy and lipid metabolisms 1,[43][44][45] . Thbs1 is present at low levels in the postnatal vessels and upregulated in various vascular diseases such as atherosclerosis 46 , ischemia reperfusion injury 47 , aortic aneurysm 13 and pulmonary arterial hypertension 48 .…”

Recent Strategies in Fabrication of Gradient Hydrogels for Tissue Engineering Applications

“…Extracellular matrix (ECM) is a complex 3D cellular microenvironment containing various proteins, proteoglycans, and biomolecules, which provide structural support for surrounding cells 8–11. The physical and biochemical cues in ECM regulate cell behaviors such as proliferation, migration, and differentiation 12–16. Over the past few decades, many researchers have focused on developing a variety of ECM mimicking scaffolds for various applications including tissue regeneration, studies of cell–material interactions, and disease model to replace animal surgery 17–19…”