(292b) Microgliosis in a Dish (Award Session)

Microgliosis, due to brain injury or disease, can lead to varying molecular and morphological changes in microglia. Magnetic resonance elastography and ultrasound studies show that brain stiffness dynamically changes with age and disease state. Molecular mechanisms that account for the stiffness predilection to brain dysfunction, specifically on microglia, during brain disorders have been underexplored, and the impact of stiffness on microglia dysfunction and alterations during brain trauma is a gap in knowledge. The central goal of this study is to understand the role of mechanotransduction (stiffness) in microglia molecular and functional remodeling leading to increase brain dysfunction risk.

In this study, we have developed an innovative biomimetic platform named “BEASTS (Bio-Engineered Adhesive Siloxane substrate with Tunable Stiffness)” based on polydimethylsiloxane (PDMS) substrate in combination with our patented polyelectrolyte multilayer film (PEM)-coating technology to engineer mechanically tunable substrates to mimic physiologic (2 kPa),; early microgliosis (8 kPa); and diseased (25 kPa) stiffness to investigate the effect of stiffness on microglia activation and function. We observed that microglia grown on soft substrates (2 kPa) displayed a consistently more quiescent phenotype while those on stiff substrates (8 kPa and 25 kPa) displayed microgliosis-like morphology. In addition to morphological changes, microglia cultured on thick substrates demonstrated a significant increase in other microgliosis hallmarks- cellular proliferation and growth. Furthermore, culturing microglia on stiff surfaces resulted in increased reactive oxygen species (ROS) production. A similar effect has been observed in microglia in brain trauma animal models and patients. These data suggest a plausible mechanism that increased stiffness modulates microglia function, causing brain injury. Our platform lends itself to the study of potential therapeutic strategies for brain injury focusing on the intricate brain microenvironment-microglia signaling pathways.