Matrix stress-relaxation and stiffness modulate oligodendrocyte differentiation

Impaired remyelination capacity, observed not only in demyelinating diseases of the central nervous system (CNS) but also in the aging brain, features a critical challenge in neural repair. Dysfunctional oligodendrocytes (OLs) are not able to efficiently restore myelin sheaths leading to increased axonal susceptibility to degeneration. Inhibitory cues to OL myelination have been described but strategies promoting remyelination keep failing. Recently acknowledged as key regulators of cellular fate and behavior, physical properties are emerging as novel potential targets in remyelination. Yet, the full extent of this impact is unknown. So far, the viscoelastic properties of the brain have been overlooked, with studies assuming that it only possesses an elastic behavior. Here, we engineered mechanically tunable 3D alginate hydrogels for culturing OLs. While being structurally biologically relevant, our matrices can be modelled in terms of elastic and viscoelastic properties. For the first time, we proved that, in addition to elasticity, viscoelasticity highly impacts the behavior of OLs. High stress-relaxation and shear moduli hydrogels lead to impaired differentiation, branching ability and metabolic activity of OLs, without visible effects on cellular viability. We showed that tuning alginate stress-relaxation properties while maintaining the stiffness triggers activation of mechanotransduction genes. Alterations were seen in genes involved in the focal adhesion kinase pathway as well as in the transcriptional factors Yap 1 and Taz and at the level of nuclear mechanotransduction (Hdac1). Understanding how microenvironmental cues support OL viability and myelination might lead to the design of improved therapies promoting remyelination. Our tunable hydrogels are not only relevant to study OL mechanobiology but can also function as a relevant model to test novel therapeutic interventions in remyelination context.