Viscoelastic microenvironment as key regulators of astrocyte behavior in brain injury and scar formation

The mechanical microenvironment plays a critical role in regulating brain development, injury repair, and the progression of neurodegenerative diseases. Despite extensive research on extracellular matrix stiffness, the effects of matrix viscoelasticity on neural cells, particularly in the context of brain injury and glial scar formation, remain elusive. In this study, we demonstrated, using an in vivo brain injury model, that matrix viscoelasticity, specifically the loss tangent, significantly increases during glial scar formation, which subsequently alters astrocyte behavior, leading to enhanced spreading and activation of reactive phenotypes. By employing an in vitro polyacrylamide hydrogel model that decouples viscosities from viscoelasticity, we reveal that microtubule dynamics, rather than actomyosin contractility, predominantly drive astrocyte responses within a viscoelastic microenvironment. These findings provide a deeper understanding of the mechanobiology of brain injuries and suggest that modulating matrix viscoelasticity could pave the way for novel mechanotherapeutic strategies to treat brain injuries and neurodegenerative diseases.