Microenvironmental Regulation of Central Nervous System Myelination and Remyelination

Both myelination and remyelination in the central nervous system (CNS) rely on the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). However, the microenvironment and underlying mechanisms of these two processes are significantly different. Myelination is driven by intrinsic developmental programs, whereas remyelination is triggered as a response to demyelinating injury. These distinct origins shape unique microenvironmental conditions that critically influence the respective processes. The microenvironment comprises, the extracellular matrix (ECM) and cellular components. Neurons, microglia, and astrocytes play stage-specific roles, ensuring proper myelin turnover under physiological conditions and regeneration after demyelination. Dysregulation of the microenvironment represents a critical driver of aberrant myelination and remyelination failure, as well as a key limitation of current pro-regenerative strategies. In this review, we discuss the cellular and molecular basis of microenvironmental regulation, recent advances in pathological microenvironmental alterations across demyelinating diseases (multiple sclerosis and neuromyelitis optica spectrum disorder) and myelin-associated disorders (Alzheimer's disease and ischemic stroke), and emerging pro-remyelination strategies targeting the microenvironment, such as Bruton's tyrosine kinase (BTK) inhibitors and microglia replacement strategies. We provide a non-cell autonomous perspective to advance the understanding of OLs differentiation and CNS remyelination.