R. Martinez Curiel, O. Tsupykov, P. Rincon Cerrada, A.-M. Al Khani, Y. Sharma, D. Martin Hernandez, E. Monni, A. Adami, E. Savchenko, L. R Rodriguez, S. Kidnapillai, A. Bruzelius, I. Hidalgo, I. Canals, G. Skibo, D. Rylander Ottosson, A. Falk, J. Bengzon, H. Ahlenius, J. Jakobsson, O. Lindvall, Z. Kokaia, S. Palma Tortosa
Intracerebral transplantation of stem cell-derived oligodendrocytes (OLs) is a promising strategy for repairing demyelinated human brain tissue, the main hallmark of white-matter disorders. However, several challenges hinder clinical translation, including slow or inefficient production of human OLs with current protocols, and difficulty in generating pure OL grafts capable of remyelinating injured neural circuits. Here, we present a robust, highly reproducible method for the rapid and efficient production of human OLs from human induced pluripotent stem cell derived long-term neuroepithelial-like stem (lt-NES) cells. Induced expression of the lineage-defining transcription factors SOX10 and OLIG2 in lt-NES cells is sufficient to generate a population of 80% OLs within 7 days. Importantly, these cells survive, differentiate and form functional OL-exclusive grafts when transplanted into adult human brain slices ex vivo, constituting the first demonstration that an OL-exclusive graft with robust myelination capacity can be generated in a clinically relevant allogeneic environment. This advance marks a significant step towards the clinical application of oligodendrocyte replacement therapy for human demyelinating disorders.