Oligodendrocytes achieve rapid signal transmission in the central nervous system by myelinating axons. To simulate the key biomechanical cues that regulate myelin formation, we developed a tunable hydrogel-based microcolumn array system that mimics the three-dimensional structure and softness of axons. This platform supports the long-term culture of oligodendrocytes and enables the robust formation of multilayer dense myelin in rodents and human oligodendrocytes. Using confocal and transmission electron microscopy, we observed a strong linear correlation between the thickness of immunostained myelin and the number of myelin wraps, thereby achieving high-content myelin quantification. Within the pathological physiological range, systematic changes in column stiffness, diameter, and surface chemistry indicate that the mechanical and geometric properties of axonal-like substrates critically regulate oligodendrocyte differentiation and myelin wrapping. Importantly, we demonstrated that drugs exhibit hardness-dependent effects on myelin formation, suggesting that overly strict in vitro models may lead to false positive drug hits. This platform provides a physiologically relevant, high-throughput detection method for dissecting oligodendrocyte biology and discovering remyelination therapies for diseases such as multiple sclerosis. This study was published in Nature Methods under the title "Targeting mechanosensitive EphA2 phase separation to alleviate arterial stiffening".
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DOI: 10.1038/s41592-026-03048-3