Oscillatory behavior of microglial cells

Abstract

Motility is critical in most physiological processes such as wound healing, cancer metastasis, and immune responses. Several studies identified cytoskeletons and associated proteins as key regulators of the cellular motility because these proteins are known to contribute in the generation of cellular forces. Despite their importance, it has been challenging to identify the roles of cytoskeletal proteins in motile properties due to the complexities in the combinatorial effects of the involved proteins. In this study, we investigate the motility of microglia, a type of immune cells in the central nervous system, which undergo a variety of phenotypic changes depending on their functional roles. In vivo, microglial cells transform their phenotypes from a ramified morphology with numerous long processes to a transitional/motile type withdrawn the processes when triggered by insults from extracellular matrix (ECM) or other cells. Due to their intrinsic scavenging roles, resting microglia move their processes or body continuously to surveil the ECM in vivo. When these cells are cultured in vitro, however, all processes are lost and only the cells with a few hand-like protrusions exist. Interestingly, the majority of the microglial cells cultured in vitro on a 2D surface feature symmetrical oscillation along their long body axis. Based on the correlation analysis, we found that the oscillation of the nucleus follows that of the leading edge of the cells with a constant delay. This might implicate that the protrusion at the leading edge is active while the nucleus is passive. We assumed this motion at the leading edge to be driven by actin protrusion forces, which can be correlated with the traction force. By the traction force microscopy, the temporal and spatial changes in the cellular traction forces were assessed where we observed highly localized tractions oscillating regularly at two ends. Furthermore, we also found the correlation with a well-defined lag between cell positions and their tractions based on which we can extract intracellular viscoelastic parameters. Putting these all together, we propose a simple viscoelastic lumped model to represent the oscillating microglial cells as a system with two masses, two springs, and two dampers in attempting to understand the dynamics of this oscillation behavior. We expect that our viscoelastic lumped model might interpret the complex cytoskeletal mechanics for the oscillatory behavior of microglial cells.