Human pluripotent stem cell-derived Schwann cells for peripheral neuropathy modeling: comparative strengths, translational gaps, and emerging 3D platforms

Abstract Background Peripheral neuropathies arise from diverse genetic and acquired insults, and Schwann cell dysfunction is central to demyelination, impaired axon-glia support, and failed regeneration. Human pluripotent stem cell (hPSC)-derived Schwann cells have emerged as a scalable and genetically defined platform for modeling these disorders in a human context. Main body This Review summarizes current hPSC-to-Schwann cell differentiation strategies and examines how these systems have been applied to model peripheral neuropathies, including Charcot-Marie-Tooth disease, neurofibromatosis type 1, diabetic peripheral neuropathy, and peripheral nerve injury. It further positions hPSC-derived Schwann cells relative to primary human Schwann cells, adult stem cell-derived Schwann-like cells, and non-human models, and discusses how emerging three-dimensional organoid, bioprinted, and microphysiological platforms address multicellular complexity and translational bottlenecks. Conclusions hPSC-derived Schwann cell models are becoming an important bridge between reductionist mechanistic studies and more physiologically complex peripheral nerve platforms. Their continued value will depend on improving maturation, functional validation, multicellular integration, and translational reproducibility.