Internalization of Exogenous Myelin by Oligodendroglia Promotes Lineage Progression

Oligodendrocytes, traditionally recognized for their role in central nervous system myelination, have emerged during the last decades as key participants maintaining brain homeostasis in response to metabolic demands and stress. In addition, injury to myelin prompts a regenerative response that leads to the formation of new myelin sheaths. However, the signals regulating effective remyelination by oligodendrocytes are still not completely understood. Here, we report that oligodendrocytes can internalize exogenous myelin both in vitro and in vivo, which leads to an increase in oligodendroglial lineage progression. RNA sequencing reveals that myelin debris alters the oligodendrocyte transcriptional profile, leading to the suppression of immune-related pathways and de novo cholesterol and fatty acid biosynthesis, while promoting lipid droplet formation for the storage and processing internalized myelin particles. In primary cultures, myelin exposure increases oligodendrocyte progenitor (OPC) proliferation and overall oligodendroglia lineage progression, accompanied by greater cellular complexity and a larger myelinated area per cell, without altering the relative OPC-to-mature oligodendrocyte ratio. Stereotaxic injection of fluorescent myelin into mouse cortex and zebrafish ventricles shows internalization by microglia and, to a lesser extent, by oligodendroglia. Notably, in the zebrafish model, ventricular injections of myelin also increase the number of ventral oligodendrocytes in the spinal cord, further supporting that myelin can promote lineage progression. These findings challenge the classical view that myelin debris intrinsically inhibits oligodendrocyte proliferation, suggesting instead that oligodendrocytes can use myelin to support self-renewal and maturation across vertebrate species, acting as a trophic factor in the absence of pathological cues.