Rapid and efficient generation of human oligodendrocytes myelinating adult human cortical neurons

Intracerebral transplantation of stem cell-derived oligodendrocytes (OLs) holds promise as a new strategy for repairing demyelinated brain tissue. However, two challenges hinder clinical translation: the slow and inefficient generation of human OLs for transplantation using the protocols described to date, and the limited insight into their remyelination potential, which has only been evaluated in vitro or in xenotransplantation studies, failing to capture critical human-specific cellular interactions involved in myelination. Here, we present a highly reproducible method for the rapid generation of myelinating human OLs from human induced pluripotent stem cell-derived long-term neuroepithelial-like stem (lt-NES) cells. Induced expression of SOX10 and OLIG2 in human lt-NES cells is sufficient to produce O4-expressing OLs with an efficiency of 80% within 7 days, as confirmed by flow cytometry and immunocytochemistry. Importantly, these OLs survive, differentiate and become functional when grafted into adult human brain slices ex vivo , demonstrating their ability to maintain their phenotype after allotransplantation in a system mimicking the clinical setting. Our new protocol has potential to further advance personalized medicine in the field of myelin disorders.