Chronic oligodendrocyte injury in central nervous system pathologies.

Types of cell death.Passive cell death; a Necrosis is a form of death where external events induce bioenergetic failure and plasma membrane breakdown, promoting the cellular contents to be released into the extracellular space, inducing an inflammatory response. Active: Regulated cell death; b Autosis is a form of excess autophagy mediated via Na+/K+-ATPase, which results in swelling and plasma membrane breakdown. c Apoptosis is regulated by the transcription factor p53 and is triggered by inflammatory mediators such as TNFα that activate the apoptosis-inducing factor mitochondria associated 1 (AIF). d Necroptosis is a form of controlled necrosis activated by death receptors like Toll-like and TNF receptor-1 (TNFR1) that act on RIPK1 and activate necroptosome forming elements, RIPK3 and MLKL. e Pyropotosis is a form of controlled cell death mediated by inflammasome activation, and triggered by hypoxia, activating gasderminD (GSDMD) leading to nuclear translocation of the programmed death ligand 1 (PDL1). f Mitochondrial permeability transition-driven necrosis is activated by metabolic stress which influences the opening of the permeability transition pore complex at the inner and outer mitochondrial membranes driven by the binding of cyclophilin D (CYPD). g Ferroptosis if a form of cell death that takes place under glutathione deficiency and induces an increase in cellular iron, altering the intracellular environment and causing lipid peroxidation. Created using BioRender.com.

OL injury in Multiple Sclerosis.a Oligodendrocytes in healthy conditions rely on nutrients (e.g., glucose), lipids (e.g., cholesterol, fatty acids), and growth factors to support their survival and myelination. b Acute-lethal injury is observed in acute MS lesions driven by cytotoxic T and NK cells (contact dependent), reactive astrocytes, microglia and increased fibrinogen. c Sub-lethal injury to oligodendrocytes in active MS lesions involves process retraction with retention of cell bodies, which can be reversed by returning them to optimal conditions. Important contributors to sub-lethal injury include metabolic stress, glutamate, and inflammatory mediators. Susceptibility to such injury may be influenced by age, and oligodendrocyte subpopulations may be specifically vulnerable. d Combination of insults and age can convert sublethal responses to progressive loss. Ongoing loss of oligodendrocytes is regulated via cell death mechanisms during disease progression, changes to the extracellular milieu such as modifications to the extracellular matrix (ECM) and presence of cytotoxic long chain fatty acids. Created using BioRender.com.

Oligodendrocyte Heterogeneity.a Remyelinating efficiency differences are observed between the gray matter and the white matter, oligodendrocytes in the former remyelinate more efficient than the latter, where oligodendrocytes have a higher capacity to differentiate. b Oligodendrocytes show regional differences, in the brain forming shorter myelin sheaths than in the spinal cord. c Oligodendrocyte differences exist during the lifespan, when during early postnatal life oligodendrocytes form compact myelin and longer myelin sheaths, and can create bridges forming sequential myelin sheaths known as ‘bridging myelin sheaths’. In adulthood and ageing, myelin sheaths are shorter and uncompact, leading to myelin unravelling and loss of the bridging myelin sheaths. Created using BioRender.com.