Multiscale Mechanobiology in Brain Physiology and Diseases

Abstract

Increasing evidence suggests that mechanics play a critical role in regulating brain function at different scales. Downstream integration of mechanical inputs into biochemical signals and genomic pathways causes observable and measurable effects on brain cell fate and can also lead to important pathological consequences. Despite recent advances, the mechanical forces that influence neuronal processes remain largely unexplored, and how endogenous mechanical forces are detected and transduced by brain cells into biochemical and genetic programs have received less attention. In this review, we described the composition of brain tissues and their pronounced microstructural heterogeneity. We discuss the individual role of neuronal and glial cell mechanics in brain homeostasis and diseases. We highlight how changes in the composition and mechanical properties of the extracellular matrix can modulate brain cell functions and describe key mechanisms of the mechanosensing process. We then consider the contribution of mechanobiology in the emergence of brain diseases by providing a critical review on traumatic brain injury, neurodegenerative diseases, and neuroblastoma. We show that a better understanding of the mechanobiology of brain tissues will require to manipulate the physico-chemical parameters of the cell microenvironment, and to develop three-dimensional models that can recapitulate the complexity and spatial diversity of brain tissues in a reproducible and predictable manner. Collectively, these emerging insights shed new light on the importance of mechanobiology and its implication in brain and nerve diseases.

Mathematical model of mechanobiology of acute and repeated synaptic injury and systemic biomarker kinetics

“…responses (Procès et al, 2022). Structural mechanics of CAMs can be simulated at various scales using molecular and coarse-grained dynamics models, spring-mass-damper models or finite element type models.…”

“…Mathematical models of synaptic mechanobiology supported by laboratory in vitro and in vivo experiments may help in better understanding of brain injury, diagnostics and protection. Mathematical modeling of CNS synaptic mechanobiology is challenging due to the immense number of brain synapses and heterogeneity of their morphologies as well as extreme range of spatial and temporal scales involved in brain injury responses ( Procès et al, 2022 ). Structural mechanics of CAMs can be simulated at various scales using molecular and coarse-grained dynamics models, spring-mass-damper models or finite element type models.…”

“…Reported mathematical models of brain-scale blast-induced biomechanics can predict local brain tissue stress-strain profiles ( Gupta et al, 2017 ). However, in spite of large volume of work on mathematical modeling of synaptic, axonal and neuronal neurotransmission, metabolism and signaling pathways very little has been reported on modeling synaptic mechanobiology ( Przekwas et al, 2016 ; Hall et al, 2021 ; Keating and Cullen, 2021 ; Hoffe and Holahan, 2022 ; Procès et al, 2022 ). In the present paper we introduce an initial formulation of a computational model of a mechanobiological “response” of a neuronal synapse to acute and repeated sub-concussive blast loads.…”

Engineered cell culture microenvironments for mechanobiology studies of brain neural cells

“…Interestingly, a closer look at different neuronal cell types reveals varying stiffness. For example, cortical neurons are softer than hippocampal neurons (30-500 Pa vs. 480-970 Pa) (Procès et al, 2022). Similarly, different stiffness values can be found among glial cells and brain regions.…”

“…For example, the lipid bilayer that forms the membrane of neurons and glial cells can deform and regain its shape in response to physical forces, allowing cells to extend and retract protrusions necessary for cell migration or withstand the forces generated during a traumatic brain injury ( Tyler, 2018 ). Similarly, the brain’s extracellular matrix can rearrange its structure after being deformed by forces imposed by neural cells ( Procès et al, 2022 ). Differences in the neural tissue’s viscoelastic properties are also found throughout the brain.…”