How single cells sense local crowding
Multicellular patterning is a hallmark of coordinated cell behaviour, typically involving intercellular communication and intracellular signal processing. The changes in the membrane lipid composition and trafficking depend on population context. The regulatory mechanism responsible for the membrane changes in adaptation to cell microenvironment has recently been a subject of intense research. The EU-funded project THE FAK-ABCA1 SYSTEM (Population context-dependent regulation of membrane lipid composition and downstream activities in mammalian cells: The FAK-ABCA1 system) studied such regulatory mechanisms. The project used single-cell microscopy over large populations, lipidomic, phosphoproteomic and microarray analysis of mice cells lacking Focal Adhesion Kinase (FAK). Typically, FAK becomes activated at low local cell density or at the edges of cell islet. This event activates signalling and gene regulation, affecting lysosomal and Golgi apparatus, and trafficking genes. The membrane protein ABCA1 (a cholesterol efflux mediator) is also strongly affected. The loss of FAK phenotype in cells can be reversed by inhibiting ABCA1, suggesting that FAK controls ABCA1 production. The project aimed to understand the role of FAK as a local crowding sensor. The results revealed that local crowding is sensed by the cell through its ability to spread and activate FAK. Scientists found that FAK indeed controls the expression of ABC transporters, impacting membrane composition and signalling. Lipidomics and microscopy showed more disordered membranes in crowded cells and more ordered membranes in sparser cells. The membrane changes lead to a general modulation of the cell's signalling state and physiology. In addition, the project developed a unique approach to simulate the dynamic behaviour of the system. The signalling processes were mathematically modelled and validated by acquisition of many single-cell data. The model successfully predicted specific patterns of active FAK and ABCA1 in populations of single cells. THE FAK-ABCA1 SYSTEM results revealed a cell-intrinsic molecular mechanism of multicellular patterning without requiring specific communication between cells. The membrane was found to be the key in the adaptation process.
Keywords
Single cells, multicellular patterning, molecular mechanism, cell behaviour, membrane lipid composition
