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Microglia mechanics: immune activation alters traction forces and durotaxis.

Bollmann L, Koser DE, Shahapure R, Gautier HO, Holzapfel GA, Scarcelli G, Gather MC, Ulbricht E, Franze K - Front Cell Neurosci (2015)

Bottom Line: 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.Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge Cambridge, UK ; Faculty of Computer Science and Biomedical Engineering, Institute of Biomechanics, Graz University of Technology Graz, Austria.

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.

No MeSH data available.


Related in: MedlinePlus

Simulated biased random walk of microglial cells migrating on a mechanical gradient. (A) Simulation for 228 cells (6 times as many as in our experiments) with a migration time distribution matching that of the experiments. Microglia were similarly biased toward the stiffer side of the substrate as found in the experiments (p > 0.1, Kuiper's test). (B) Simulation for 1000 cells migrating 1000 min. On longer time scales, cells showed a robust migration toward the stiffer side of the gradient (p < 0.01, Kuiper's test).
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Figure 10: Simulated biased random walk of microglial cells migrating on a mechanical gradient. (A) Simulation for 228 cells (6 times as many as in our experiments) with a migration time distribution matching that of the experiments. Microglia were similarly biased toward the stiffer side of the substrate as found in the experiments (p > 0.1, Kuiper's test). (B) Simulation for 1000 cells migrating 1000 min. On longer time scales, cells showed a robust migration toward the stiffer side of the gradient (p < 0.01, Kuiper's test).

Mentions: To account for the dependence of the step length on the turning angle φ, we applied the φ-dependent fitting parameters of the Burr distributions used in Figure 9. The results of our simulation closely matched our experimental findings. Endpoints were strongly biased toward the stiffer side of the gradient (Figure 10), with a non-uniform circular distribution (p < 10−12, Rayleigh test). Furthermore, both the angular distribution of endpoints (p > 0.1, Kuiper's test) and their coordinates were similar to our experimental data (p > 0.05 and p > 0.85 for the coordinates perpendicular and along the gradient, respectively, Mann Whitney U-test). While the contour velocity was similar (1.30 μm/min, p > 0.10), the directness D was lower compared to the experimental data (0.44; p < 10−3). Accordingly, also the Euclidean velocity was significantly reduced (0.47 μm/min, p < 10−3). However, when we adapted the number of simulated cells to that of the experiments (N = 38) and matched the stalling percentage distributions, the directness was similar (0.55; p > 0.25). Hence, a biased random walk model approximates our experimental findings very well.


Microglia mechanics: immune activation alters traction forces and durotaxis.

Bollmann L, Koser DE, Shahapure R, Gautier HO, Holzapfel GA, Scarcelli G, Gather MC, Ulbricht E, Franze K - Front Cell Neurosci (2015)

Simulated biased random walk of microglial cells migrating on a mechanical gradient. (A) Simulation for 228 cells (6 times as many as in our experiments) with a migration time distribution matching that of the experiments. Microglia were similarly biased toward the stiffer side of the substrate as found in the experiments (p > 0.1, Kuiper's test). (B) Simulation for 1000 cells migrating 1000 min. On longer time scales, cells showed a robust migration toward the stiffer side of the gradient (p < 0.01, Kuiper's test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4585148&req=5

Figure 10: Simulated biased random walk of microglial cells migrating on a mechanical gradient. (A) Simulation for 228 cells (6 times as many as in our experiments) with a migration time distribution matching that of the experiments. Microglia were similarly biased toward the stiffer side of the substrate as found in the experiments (p > 0.1, Kuiper's test). (B) Simulation for 1000 cells migrating 1000 min. On longer time scales, cells showed a robust migration toward the stiffer side of the gradient (p < 0.01, Kuiper's test).
Mentions: To account for the dependence of the step length on the turning angle φ, we applied the φ-dependent fitting parameters of the Burr distributions used in Figure 9. The results of our simulation closely matched our experimental findings. Endpoints were strongly biased toward the stiffer side of the gradient (Figure 10), with a non-uniform circular distribution (p < 10−12, Rayleigh test). Furthermore, both the angular distribution of endpoints (p > 0.1, Kuiper's test) and their coordinates were similar to our experimental data (p > 0.05 and p > 0.85 for the coordinates perpendicular and along the gradient, respectively, Mann Whitney U-test). While the contour velocity was similar (1.30 μm/min, p > 0.10), the directness D was lower compared to the experimental data (0.44; p < 10−3). Accordingly, also the Euclidean velocity was significantly reduced (0.47 μm/min, p < 10−3). However, when we adapted the number of simulated cells to that of the experiments (N = 38) and matched the stalling percentage distributions, the directness was similar (0.55; p > 0.25). Hence, a biased random walk model approximates our experimental findings very well.

Bottom Line: 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.Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Development and Neuroscience, University of Cambridge Cambridge, UK ; Faculty of Computer Science and Biomedical Engineering, Institute of Biomechanics, Graz University of Technology Graz, Austria.

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.

No MeSH data available.


Related in: MedlinePlus