A novel in vitro model for investigating oligodendroglial maturation and myelin deposition under demyelinating and remyelinating conditions: Impact of microglial depletion and repopulation.

Experimental models of multiple sclerosis (MS) have significantly contributed to our understanding of pathophysiology and the development of therapeutic interventions. Various in vivo animal models have successfully replicated key features of MS and associated pathophysiological processes, shedding light on the sequence of events leading to disease initiation, progression, and resolution. Nevertheless, these models often entail substantial costs and prolonged treatment periods. In contrast, in vitro models offer distinct advantages, including cost-effectiveness and precise control over experimental conditions, thereby facilitating more reproducible results. We have developed a novel in vitro model tailored to the study of oligodendroglial maturation and myelin deposition under demyelinating and remyelinating conditions, which encompasses all the cell types present in the central nervous system (CNS). Of note, our model enables the evaluation of microglial cell commitment through a protocol involving their depletion and subsequent repopulation. Given that the development and survival of microglia are critically reliant on colony-stimulating factor-1 receptor (CSF-1R) signaling, we have employed CSF-1R inhibition to effectively deplete microglia. This versatile model holds promise for the assessment of potential therapies aimed at promoting oligodendroglial differentiation to safeguard and repair myelin, hence mitigate neurodegenerative processes.

Microglia depletion as a therapeutic strategy: friend or foe in multiple sclerosis models?

Multiple sclerosis is a chronic central nervous system demyelinating disease whose onset and progression are driven by a combination of immune dysregulation, genetic predisposition, and environmental factors. The activation of microglia and astrocytes is a key player in multiple sclerosis immunopathology, playing specific roles associated with anatomical location and phase of the disease and controlling demyelination and neurodegeneration. Even though reactive microglia can damage tissue and heighten deleterious effects and neurodegeneration, activated microglia also perform neuroprotective functions such as debris phagocytosis and growth factor secretion. Astrocytes can be activated into pro-inflammatory phenotype A1 through a mechanism mediated by activated neuroinflammatory microglia, which could also mediate neurodegeneration. This A1 phenotype inhibits oligodendrocyte proliferation and differentiation and is toxic to both oligodendrocytes and neurons. However, astroglial activation into phenotype A2 may also take place in response to neurodegeneration and as a protective mechanism. A variety of animal models mimicking specific multiple sclerosis features and the associated pathophysiological processes have helped establish the cascades of events that lead to the initiation, progression, and resolution of the disease. The colony-stimulating factor-1 receptor is expressed by myeloid lineage cells such as peripheral monocytes and macrophages and central nervous system microglia. Importantly, as microglia development and survival critically rely on colony-stimulating factor-1 receptor signaling, colony-stimulating factor-1 receptor inhibition can almost completely eliminate microglia from the brain. In this context, the present review discusses the impact of microglial depletion through colony-stimulating factor-1 receptor inhibition on demyelination, neurodegeneration, astroglial activation, and behavior in different multiple sclerosis models, highlighting the diversity of microglial effects on the progression of demyelinating diseases and the strengths and weaknesses of microglial modulation in therapy design.