Dynamics and Impact of Repopulating Microglia Following Oligodendroglial Damage

Multiple sclerosis is a chronic inflammatory and demyelinating disease that primarily affects young adults. Active demyelination and neurodegeneration have been associated with early microglial and astroglial activation. While reactive microglia (MG) can contribute to tissue damage and exacerbate neurodegeneration, they also play a neuroprotective role by clearing debris through phagocytosis and secreting growth factors that support repair. The aim of this study was to evaluate the effects of MG depletion and repopulation on the response to lysophosphatidylcholine-induced oligodendroglial damage using an in vitro model previously characterized by our laboratory. Since microglial development and survival critically depend on colony-stimulating factor-1 receptor (CSF-1R) signaling, we employed CSF-1R inhibition with BLZ945 to effectively deplete MG. Results show that repopulation occurs even in demyelinating conditions and, at early time points, results in MG exhibiting a morphology indicative of a less activated phenotype. Despite having higher phagocytic activity, early repopulating MG are few and thus unable to efficiently clear myelin debris. However, these repopulating MG still demonstrated to induce oligodendroglial differentiation. Studies using conditioned media revealed that early repopulating MG release factors into the environment which promote oligodendroglial progenitor cell viability and facilitate oligodendroglial differentiation in a demyelinating context, an effect not observed in neurons. Interestingly, our in vitro results show a close correlation with in vivo findings previously reported and demonstrate the relevance of our model in developing therapies for demyelinating diseases. These findings underscore both the potential and limitations of microglial modulation aimed at eliminating pro-inflammatory profiles and promoting repopulation with pro-regenerative characteristics.