The Chinese University of Hong Kong (CUHK), Hong Kong
Abstract: Ageing causes deterioration of tissue regeneration capacity due to declined function of stem cells and progenitor cells, such as oligodendrocyte progenitor cells (OPC). With age, OPCs gradually lose their proliferation and differentiation capacities, resulting in accelerated myelin loss and cognitive decline which are associated with the development of neurodegenerative diseases. OPCs reside in extracellular matrix (ECM), and interestingly, the mechanical properties of ECM in the brain change with age, contributing to the dysfunction of brain cells. However, the question of how stiffness regulates OPC functions remains largely unknown. Recent studies have identified various modulators that regulate OPC functions during aging. However, the intricate interplay between mechanical and intrinsic modifications in regulating the molecular and cellular functions of OPCs remain poorly understood. To bridge this knowledge gap, we have developed a hydrogel model that recapitulates the age-related mechanical changes of brain ECM. Our findings indicate stiffness has a profound impact on the cellular functions of OPCs. Coupling with comprehensive data mining analyses, we found ageing impairs ECM-related functions in the brain of aged mice, and adversely affects OPC functions. We also identified a specific mechanosensitive ion channel target which is functionally expressed in OPCs and exhibits increased expression in response to higher stiffness level. Notably, either overexpression or enhanced functionality of this channel leads to age-related changes in OPCs, indicating its potential role in the aging process at the cellular level. The study advances the understanding of the influence of mechanical properties of ECM to OPC functionality. The identification of mechanosensitive ion channel paves the way for novel therapeutic strategies which aim at enhancing OPC functions within the context of ageing. By targeting the mechanical properties of the ECM or modulating mechanosensitive pathways, it is possible to rejuvenate OPC and restore remyelination capacities in age-related neurological disorders, thereby profoundly impacting on myelin repair and overall brain health.
