Abstract
Microglial cells are key players in the primary immune response of the central nervous system. They are highly active and motile cells that chemically and mechanically interact with their environment. While the impact of chemical signaling on microglia function has been studied in much detail, the current understanding of mechanical signaling is very limited. When cultured on compliant substrates, primary microglial cells adapted their spread area, morphology, and actin cytoskeleton to the stiffness of their environment. Traction force microscopy revealed that forces exerted by microglia increase with substrate stiffness until reaching a plateau at a shear modulus of ~5 kPa. When cultured on substrates incorporating stiffness gradients, microglia preferentially migrated toward stiffer regions, a process termed durotaxis. Lipopolysaccharide-induced immune-activation of microglia led to changes in traction forces, increased migration velocities and an amplification of durotaxis. We finally developed a mathematical model connecting traction forces with the durotactic behavior of migrating microglial cells. Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies. Stiffness gradients in tissue surrounding neural implants such as electrodes, for example, could mechanically attract microglial cells, thus facilitating foreign body reactions detrimental to electrode functioning.
Highlights
The central nervous system (CNS) is separated from the systemic immune system by the blood–brain barrier, which protects the tissue from most infections
Cell Morphology Changes with Substrate Stiffness To investigate how microglia mechanically interact with their environment, we first investigated how their morphology changes with substrate stiffness
The spread area of primary microglial cells significantly increased with substrate stiffness (p < 0.05, Kruskal-Wallis ANOVA) (Figure 1)
Summary
The central nervous system (CNS) is separated from the systemic immune system by the blood–brain barrier, which protects the tissue from most infections. When pathogens cross the blood-brain-barrier, after brain lesions, or in any other CNS dysfunction, microglial cells form the first line of immune defense. Chemical interactions of microglial cells with their environment have been extensively studied in the past. In order to migrate, microglia need to exert forces on their environment. While they exert forces on the surrounding tissue, they probe its mechanical properties (Franze et al, 2013). Forces exerted by microglial cells have not been measured, and their mechanical interactions with their environment are currently poorly understood
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