A human iPSC-Derived myelination model for investigating fetal brain injuries

Abstract

Cerebral white matter injuries, such as periventricular leukomalacia, are major contributors to neurodevelopmental impairments in preterm infants. Despite the clinical significance of these conditions, human-relevant models for studying fetal brain development and injury mechanisms remain limited. This study introduces a human iPSC-derived myelination model developed using a microfluidic device. The platform combines spinal cord-patterned neuronal and oligodendrocyte spheroids to recapitulate axon-glia interactions and myelination processes in vitro. The model successfully achieved axonal fascicle formation and compact myelin deposition, as validated by immunostaining and transmission electron microscopy. Functional calcium imaging confirmed neuronal activity within the system, underscoring its physiological relevance. While myelination efficiency was partial, with some axons remaining unmyelinated under the current conditions, this model represents a significant advancement in human myelin biology, offering a foundation for investigating fetal and perinatal brain injuries and related pathologies. Future refinements, such as improved myelination coverage and incorporating additional CNS cell types, will enhance its utility for studying disease mechanisms and enabling high-throughput drug screening.