The myelin sheath produced by oligodendrocytes is essential for rapid neural signal transmission and long-term axonal integrity. Disruption of myelin-whether from oligodendrocyte dysfunction or chronic neuroinflammation-leads to impaired communication and axonal degeneration underlying disorders such as Multiple Sclerosis (MS), ALS, Alzheimer's disease, and Huntington's disease. Current mechanistic understanding of human myelination remains limited because existing in-vitro systems lack physiological architecture, perfusion, or reproducibility. Two-dimensional cultures fail to support realistic neuron-glia interactions, while traditional 3D hydrogels restrict neurite extension and prevent long-range axonal-oligodendrocyte contact necessary for myelination. Brain organoids improve cellular diversity but suffer from structural heterogeneity, poor nutrient transport, and limited accessibility, preventing controlled study of myelin formation and injury.
This proposal addresses these barriers by developing a perfusable engineered human neural tissue using microporous microgel assemblies that allow iPSC-derived neural stem cells to occupy interconnected pore spaces rather than being encapsulated in a dense matrix. This architecture enables long-range neurite outgrowth, oligodendrocyte-axon interactions, and efficient nutrient exchange under microfluidic perfusion. In this research, we will establish a mature, myelinating human neural tissue through systematic optimization of scaffold parameters, adhesive cues, and flow conditions. Once this project is completed, MS-related inflammatory demyelination will be simulated by delivering pro-inflammatory cytokines or reactive oxygen species into the culture chamber in a controlled manner.
The resulting platform will provide the first reproducible, physiologically relevant human 3D model capable of forming stable myelin. This system will enable mechanistic dissection of human myelination and demyelination and establish the foundation for future studies on neuroinflammatory disease pathways and remyelination therapies.
This research develops a physiologically realistic human neural tissue model to improve understanding of how myelin forms and is damaged during neuroinflammatory diseases such as multiple sclerosis. By enabling controlled study of myelination and potentially demyelination in a human-relevant system, the project will help identify mechanisms that contribute to neurological disability and support future efforts to develop therapies that preserve or restore myelin.
