Oligodendrocytes (OLs) and Ischemic Brain Injury
At a glance
In the central nervous system (CNS), oligodendrocytes (OLs) are responsible for myelination of axons, which is critical to maintain normal-structure of axon. After ischemic strokes, OLs are particularly susceptible to oxygen and nutrient deprivation; therefore they may become necrotic. The injury of OLs can finally cause demyelination and disturbance in myelinogenesis, which may impair the abilities of axons to conduct electric impulses properly through affecting their function operationally or structurally at various levels from metabolism damage processes to more severe decline that eventually causes a worst fatality state; most importantly long-standing neurologic disabilities emerged following white matter injuries. Adult-onset stroke, periventricular leukomalacia, and post-stroke cognitive impairment primarily target OLs, making them a critical therapeutic target.
We will discuss the biology and function of OLs under physiological conditions, ischemic stroke-induced damage to OLs and finally reveal the potential of oligodendrocyte-based therapy for treating ischemic stroke.
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The Biology of OLs
The Function of OLs
OLs originate from small populations cells within the CNS comprising 5–10% of the total glial pool. Oligodendrocyte precursor cells (OPCs) proliferate and differentiate into mature OLs for remyelination. OLs and OPCs play important roles, including forming myelin sheaths around CNS axons, supporting axonal metabolism, and mediating certain forms of neuroplasticity.
The principal function of OLs is to generate myelin. OLs give off processes that enwrap the internodal segments of axons to form the myelin sheath that facilitates fast conduction of nerve impulses. Myelination is essential for various neurological functions, including motor learning and social behavior. Additionally, OLs are crucial to axonal integrity and provide metabolic support to axons independent of their myelination capabilities.
OLs also have non-myelinating functions, particularly OPCs, which have immunomodulatory capacity as they express cytokine receptors and survey their microenvironment through filopodia extension. In response to inflammatory cues, OPCs can migrate to sites of injury and exhibit a proinflammatory phenotype that may negatively affect recovery after injury.
Oligodendrocyte Markers
Identification of OL damage in white and gray matter is crucial for understanding white matter pathology, but is challenging due to the complexity of histologic assessment, particularly after ischemic injury. Traditional histochemical methods may not effectively detect partial injury or provide timely results. Therefore, more specific markers and techniques are needed for accurate assessment.
Several antibodies targeting OL components, such as myelin proteins (e.g., MBP, PLP) and cell surface sphingolipids (e.g., galactocerebroside), have been utilized in ischemia models. Other markers, like glial cell markers and mRNA hybridization for specific genes (e.g., PLP), offer additional identification options, though none have achieved universal acceptance due to variation in what they label and a loss of markers during injury. Notably, OLs in both ischemic rat and human brains exhibit immunoreactivity for the cytoskeletal protein tau, providing a potential method for quantifying OL damage and evaluating therapeutic interventions by assessing tau-positive cells and their spatial distribution.
Ischemic Stroke Induces Oligodendrocyte Injury
Intrinsic Susceptibility of OLs to Ischemic Insults
Ischemic stroke preferentially affects oligodendrocytes over other glial cells in the central nervous system due to several OL-specific characteristics that make them more prone to ischemia-induced excitotoxic white matter injury. These include high iron content, low levels of reduced glutathione and are predominantly oxidative in metabolism with lipids/sphingolipids abundant but also possess a vulnerability through their permeability to binding by the excitotoxic amino acid Glutamate.
Fig.1. Features of OLs which render them vulnerable to ischemic insults. (Huan, et al., 2023)
Mechanisms of OL Injury
Ischemic stroke causes oligodendrocyte injury, which results in demyelination, leading to axon instability, decreased neuronal liveliness and contributing to long-term neurological disease. White matter injury associated with altered OL phenotype and myelin loss occurs very soon after an ischemic insult and can gradually progress over time, to cause problems such as vascular dementia.
The mechanisms of oligodendrocyte injury during ischemia, including oxidative stress, inappropriate trophic factor signaling, excitotoxicity, and immune-mediated responses, have been identified in in vitro and in vivo studies. Additionally, the interactions between OLs and others cells in neurovascular unit (NVU), including astrocytes, microglia neurons and endothelial cell are crucial for the recovery of OLs after ischemic injury but their specific mechanisms have not been well demonstrated. Future studies are warranted for a more comprehensive understanding of such interactions, as well the identification of additional treatment targets in ischemic stroke.
Fig.2. Potential mechanisms of oligodendrocyte injury after hypoxia or ischemia. (Dewar, et al., 2003)
Protective Strategies for OLs Injury in Ischemic Stroke
To evaluate whether potential anti-ischemic agents can mitigate oligodendrocyte damage in animal stroke models, it's crucial to employ techniques that quantify the degree of pathology. As mentioned earlier, a quantitative assessment of oligodendrocyte injury can be achieved by measuring tau immunoreactivity following ischemic events. We present several therapeutic strategies for OLs injury in ischemic stroke.
Neurotransmitter Mediated Injury
Therapeutic approaches to prevent OLs, OPCs and neurons from excitotoxic lesion include antagonists of AMPA receptor, NMDA receptor, P2X7 receptor or glutamate transporters (GluTs) as well an inhibitors of Adenosine A2A receptors.
Oxidative Stress in OLs
Antioxidants have been highlighted as a potential protective measure against oxidative damage in cultured OLs, indicating their possible role in safeguarding both gray and white matter in vivo. For supporting this evidence, a study where pretreatment with the spin-trap agent α-phenyl-tert-butyl-nitrone significantly reduced the amount of oligodendrocyte pathology induced by focal cerebral ischemia.
Regulating Neighboring Glial Cells
Ischemia causes neuroinflammation as well as the activating of microglia and astrocytes, therefore anti-inflammation therapy may be a promising treatment for remyelination.
Targeting OLs
Targeting OLs, myelin, and their receptors to attenuate ischemia injury and establish functional recovery after stroke. The further research is needed for the development and optimization of these therapeutic strategies. This will mean revealing new therapeutic approaches, improving drug delivery and testing with maximum safety the benefit of therapies preclinically followed by minimal-risk trials in patients.
- Huang, S., et al. (2023). New insights into the roles of oligodendrocytes regulation in ischemic stroke recovery. Neurobiology of disease, 184, 106200.
- Dewar, D., et al. (2003). Oligodendrocytes and ischemic brain injury. Journal of Cerebral Blood Flow & Metabolism, 23(3), 263-274.
