# Internalization of Exogenous Myelin by Oligodendroglia Promotes Lineage Progression

## TL;DR

Oligodendrocytes can internalize myelin debris, which promotes their growth and development, challenging previous assumptions about myelin's role in the brain.

## Contribution

The study reveals that myelin debris acts as a trophic factor promoting oligodendrocyte lineage progression across vertebrates.

## Key findings

- Oligodendrocytes internalize exogenous myelin in vitro and in vivo.
- Myelin debris alters oligodendrocyte transcription, promoting lipid metabolism and lineage progression.
- Myelin exposure increases oligodendrocyte progenitor proliferation and myelinated area per cell.

## Abstract

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.

Oligodendroglia internalize extracellular myelin debris in vitro and in vivo.Internalized myelin modulates lipid metabolism and lipid droplet formation.Myelin‐derived signals promote oligodendroglial proliferation and lineage progression.

Oligodendroglia internalize extracellular myelin debris in vitro and in vivo.

Internalized myelin modulates lipid metabolism and lipid droplet formation.

Myelin‐derived signals promote oligodendroglial proliferation and lineage progression.