Something's wrong in the (cellular) neighborhood: Mechanisms of epithelial wound detection

Speaker: 
Shane Hutson
Date: 
Wed, Jul 15, 2020
Location: 
Zoom
Conference: 
Mathematical Biology Seminar
CRG: 
Abstract: 

The first response of epithelial cells to local wounds is a dramatic increase in cytosolic calcium. This increase occurs quickly – calcium floods into damaged cells within 0.1 s, moves into adjacent cells over ~20 s, and appears in a much larger set of surrounding cells via a delayed second expansion over 40-300 s – but calcium is nonetheless a reporter: cells must detect wounds even earlier. Using the calcium response as a proxy for wound detection, we have identified an upstream G-protein-coupled-receptor (GPCR) signaling pathway, including the receptor and its chemokine ligand. We present experimental and computational evidence that multiple proteases released during cell lysis/wounding serve as the instructive signal, proteolytically liberating active ligand to diffuse to GPCRs on surrounding epithelial cells. Epithelial wounds are thus detected by the activation of a protease bait. We will discuss the experimental evidence and a corresponding computational model developed to test the plausibility of these hypothesized mechanisms. The model includes calcium currents between each cell’s cytosol and its endoplasmic reticulum (ER), between cytosol and extracellular space, and between the cytosol of neighboring cells. These calcium currents are initiated in the model by cavitation-induced microtears in the plasma membranes of cells near the wound (initial influx), by flow through gap junctions into adjacent cells (first expansion), and by the activation of GPCRs via a proteolytically activated diffusible ligand (second expansion). We will discuss how the model matches experimental observations and makes experimentally testable predictions.

Supported by NIH Grant 1R01GM130130.

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