The Oligodendrocytes in Brain Ischemia-Reperfusion Injury: Comparison
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Please note this is a comparison between Version 4 by Maria José Pérez Alvarez and Version 3 by Conner Chen.

Oligodendrocytes are the responsible cells for axon myelination in the central nervous system. Oligodendrocytes are especially sensitive to oxidative stress and excitotoxicity generated during brain ischemia.

  • the central nervous system
  • Oligodendrocytes
  • glia
  • brain ischemia

1. Oligodendrocytes

Oligodendrocytes are the responsible cells for axon myelination in the central nervous system. A correct myelination is crucial for correct nerve impulse transmission and electrical isolation of axons, but it also determines the axon diameter and helps in the maintenance of axonal stability, and thus neuronal viability [1][2][3].
In the adult brain, mature oligodendrocytes are spawned from oligodendrocyte progenitor cells (OPC) following a tightly coordinated process that includes migration, proliferation and differentiation. OPCs represent 5–8% of total adult brain glial cells and they are characterized by the expression of the neuron/glial antigen 2 (NG2) and platelet-derived growth factor receptor alpha (PDGFRA). They could play an important role in remyelination, as they show the ability to proliferate and differentiate after a demyelinating insult [4].
Pre-oligodendrocytes are the next maturation step and are characterized by expression of the cell surface markers O4 and O1 [5][6] and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase). At this differentiation stage, pre-oligodendrocytes connect with target axons, losing their bipolar form, and they start to build filamentous myelin outgrowths [2].
The main feature of mature oligodendrocytes is the production of mature and fully functional myelin, thus they are typically identified by the expression of myelin basic protein [7], transmembrane proteolipid protein [8], myelin associated glycoprotein [9], galactocerebroside [10], and myelin-oligodendrocyte glycoprotein [7].
Apart from myelin formation, there is evidence pointing to non-myelinating functions of oligodendrocytes, specifically of OPCs, that have shown certain immunomodulatory capacity and express cytokine receptors (Kirby et al., 2019). OPCs assess their environment through constant filopodia extensions [3] and, as microglia and astrocytes, they migrate to injured sites and acquire a pro-inflammatory phenotype that could negatively affect recovery after injury [11][12]. OPCs exposed to IFN-γ present high expression levels of MHC-I receptor and present antigens to cytotoxic T cells [12]. In addition, using in vitro and in vivo models of inflammatory demyelinating diseases, IFN-γ has been shown to inhibit differentiation into mature oligodendrocytes and myelination [13][14].

2. Oligodendrocyte Response to Ischemia

Most of the studies related to the effects of cerebral I/R in the CNS have focused on the gray matter, neglecting the effects in white matter. However, white matter damage is an important component to consider in ischemic stroke pathology, not only because of the direct negative effect of ischemia on this tissue [15][16], but also because of the indirect effect on the rest of the brain tissues given the potential role of white matter in tissue repair.
Brain ischemia causes severe damage to white matter, especially in the ischemic core. This white matter damage accounts for almost half of the infarct volume and is a major cause of functional disability and cognitive dysfunction [17][18]. Some recent reports suggest that changes in white matter infarct volume, particularly in the deep subcortical area, have clinical relevance as predictors of long-term severity after cerebral ischemia [19][20]. Interestingly, animal stroke models have revealed that the degree of white matter vulnerability to such insults strongly depends on age, with juvenile animals being more resistant to injury than perinatal or older animals [21][22], suggesting that different mechanisms of white matter injury are implicated in each developmental period.
Many reports show that preserving the integrity of white matter reduces neuronal injury and ameliorates neurological function [23][24]. Taking into account that disturbance of white mater is a direct reflect of oligodendrocytes perturbations, preserving their viability after stroke should enhance neurological recovery after brain ischemia.
It is known that oligodendrocytes are especially sensitive to ischemic damage in short-term periods owing to the high energy rate required for axon myelination, high intracellular iron levels, and low expression of certain antioxidant enzymes [25][26]. In the early stages of stroke, an increase in oxidative stress occurs, especially after reperfusion. This situation induces oligodendrocyte damage followed by tissue demyelination and thus axonal destabilization, affecting neuronal viability and promoting long-term neurological dysfunctions [27]. Oligodendrocytes exposed to hypoxia show a great production of superoxide radical, lipid peroxidation, and iron oxidation [25]. Using in vivo models of focal cerebral ischemia, it has been observed that, as early as 3 h after ischemia induction, oligodendrocytes start to show signs of swelling and can be lethally injured [16]. These changes precede neuronal injury by several hours, suggesting that white matter is more vulnerable to ischemic damage than gray matter at early phases of stroke. Besides, it has been demonstrated that NG2+ cells are more assailable than neurons or astrocytes during early reperfusion after 3 h of MCAO [28]. Other histopathological indicators of white matter damage after ischemia include segmental swelling of myelinated axons and the development of vacuoles between the myelin sheath and axolemma, indicating myelin destabilization [16][29]. It is known that antioxidants reduce ischemic damage. Administration of Ebselen right after reperfusion significantly reduced axonal and oligodendrocyte damage and improved neurological deficits in MCAO models [30].
Glutamate and ATP contribute to oligodendrocyte damage and injury of white matter [31]. As previously mentioned, extracellular levels of both neurotransmitters highly increase during ischemia above physiological levels, which triggers oligodendrocyte damage. Oligodendrocytes present functional AMPA and kainate glutamate receptor in their soma, while NMDA receptors can be detected in their processes [32][33]. The overactivation of these receptors enhances ischemic damage inflicted to oligodendrocytes through excitotoxicity [22][33]. On the contrary, glutamate receptor antagonists partially protect oligodendrocytes from ischemic injury and reduce white matter damage [34].
In parallel, ATP is released during ischemic events through the opening of pannexin-1 channels in a sufficient amount to activate low affinity receptors. Oligodendrocytes express low affinity P2X7Rs at relatively high levels [35]. ATP activation of P2X7Rs causes oligodendrocyte damage. Blocking these ATP receptors after MCAO has been shown to be protective against ischemic damage, not only preserving oligodendrocytes viability, but also maintaining the composition and functionality of axon initial segment, which promotes neuronal health in the injured area [36][37].

3. Oligodendrogenesis

Some studies highlight that cerebral ischemia induces an alternative long-term response of oligodendrocytes consistent in an increase of the cell population mainly at the ischemic area [38][39][40]. In other words, cerebral ischemia induces oligodendrogenesis, probably as a protective mechanism of self-repair in response to damage. As oligodendrocytes are damaged in the short term after ischemia, a successful replacement of damaged and lost oligodendrocytes with newly generated ones is essential for remyelination after brain injuries. Until very recently, the underlying mechanism and the origin of these new oligodendrocytes was poorly understood. These new oligodendrocytes may proceed from maturation/differentiation of a pool of precursors from two different origins: newly generated precursors from the subventricular zone (SVZ) or pre-existing NG2+ cells located in the gray matter that undergo differentiation. An increment of NG2+ cells in the penumbra region [4][21] in parallel with a significant reduction of these cells in the ischemic core after reperfusion has been observed in tMCAO models [41]. In addition, a study reported a significant increment in a special subpopulation of oligodendrocytes (Olig2+ cells) expressing 3R-Tau in the SVZ at 5 and 21 days after pMCAO [38]. These data indicate that oligodendrogenesis exists after ischemia independently of reperfusion. It can be proposed that some of these new oligodendrocytes could proceed from newly generated cells resulting from post-ischemic division in the SVZ during the first 6 h of stroke [38].
Therefore, ischemia induces cell division at SVZ and some of these newly generated cells become oligodendrocytes with the ability to migrate towards the damaged area, specially to peri-infarct regions; differentiate into mature oligodendrocytes; and promote partial tissue remyelination [38][41]. Although ischemic rats spontaneously recover neurological functions coinciding with an increment of Olig2+ cells in the ischemic area, neurodegenerative damage can still be detected long after the stroke episode. This suggests that neither the differentiation to mature oligodendrocytes nor the remyelination process are completely successful in restoring the histological structure, but they suffice for recovering certain neurological function [38][42].
Therefore, potentiating oligodendrocyte response to ischemic damage could be a good therapeutic strategy to ameliorate cognitive and motor disabilities induced by stroke. In line with this, treatments that promote oligodendrogenesis have been shown to enhance white matter repair and to reduce ischemic damage [24][43]. TGF-α increases after tMCAO in neurons and glial cells including oligodendrocytes. This effector directly protects oligodendrocytes from cell death induced by OGD, thereby maintaining white matter integrity and improving neurological recovery after stroke [23]. Accordingly, TGF-α-deficient mice showed long-term exacerbation of sensorimotor deficits after tMCAO accompanied by loss of white matter integrity [23]. Interestingly, administration of valproic acid, an antiepileptic drug, starting 24 h after MCAO, also increased oligodendrocyte survival and improved neurological outcome, associated with an increment in myelinated axons density in the penumbra [44].
In view of this evidence, it can be concluded that cerebral ischemia induces oligodendrocyte death as a consequence of excitotoxicity and oxidative stress, while oligodendrogenesis is probably triggered as a defense mechanism to damage. These newly generated oligodendrocytes colonize penumbra area with a still unknown role.
Some authors suggest that these newly generated cells are in part NG2+ OPCs that never reach a mature state [45]. Alternatively, others authors propose that oligodendrogenesis could be a brain self-repair response triggered after ischemia in an attempt to myelinate injured axons or even promote neuronal survival by creating an optimal environment. Moreover, recent data demonstrated vascular effects of some newly generated oligodendrocytes. OPCs populations are heterogeneous and present different phenotypes, which give them multiples roles under pathological and non-pathological conditions. Apart from their regional variations, OPCs can classified by the base of their spatial relation to brain vasculature into perivascular, parenchymal, and intermediate. Perivascular ones are part of the so-called “neurovascular unit”. In a recent work, a subpopulation of newly generated OPCs after ischemia has been described, belonging to perivascular OPCs, that facilitates post-stroke angiogenesis, thereby improving functional recovery in a model of tMCAo [45]. The “vascular” effects of OPCs have been confirmed using OPCs’ transplantation in in vivo models of focal cerebral ischemia, which promotes integrity of the BBB by a reduction of leakage in the acute phase of ischemic stroke, alleviates edema, and improves neurological recovery after ischemic stroke [46]. These results point out an important vascular effect of newly generated OPCs after ischemia that would be interesting to enhance in order to improve tissue recovery through the functionality retrieval of the vascular unit.
Alternative approaches that stimulate OPCs’ division in adult brain after MCAO, such as bone marrow stromal cells’ (BMSCs) transplantation, showed improvement of remyelination [47][48]. Furthermore, using in vitro models has revealed that co-culture of BMSCs with oligodendrocytes increased oligodendrocyte protection by providing growth factors through activation of PI3K/Akt pathway. [49]. These results point out that cellular therapy based on transplantation of OPCs or BMSCs could be a new therapeutic approximation to cerebral ischemia focused in the restoration of white matter function.
Usually, myelin has been considered an immutable structure, but recent reports have revealed that myelin sheath can change throughout the lifespan, showing that myelination is not a static process [50]. Neuronal activity can affect proliferation and differentiation of oligodendrocytes [51]. Therefore, therapies aimed at increasing neuronal activity of the damaged area, such as physical exercise, improve the quality of life of patients and the overall health of their white matter. Physical exercise is known to induce newly generated OPCs or mature oligodendrocytes via activation of CREB/BDNF in a model of neonatal hypoxia-reperfusion [52]. In addition, exercise enhanced myelin repair by upregulating the Wnt/β-catenin signaling pathway and reduced infarct volume after brain ischemia in juvenile or adult rats [53].

4. Interaction with Other Glial Cells

As previously mentioned, ischemia induces neuroinflammation with a concomitant activation of microglia and astrocytes. Astrocyte-derived BDNF promotes not only neuron viability, but also oligodendrogenesis [54], and induces differentiation of OPCs into mature oligodendrocytes [55]. Conversely, in an in vivo model of ischemia, Sozmen et al. [56] showed that reactive astrocytes, probably belonging to the A1 subpopulation, blocked proliferation and differentiation of OPCs. This evidence supports the idea that A2-astrocytic phenotype, as opposed to A1, could reduce ischemic damage through an increase in functional oligodendrocytes number.
The relationship between microglia and oligodendrocytes after brain ischemia is similar to that observed for astrocytes. The population of microglia that colonizes ischemic area is able to induce a reduction of OPCs [50], but also to promote differentiation of OPCs [57]. This dual effect depends on the predominant microglial subpopulation in the damaged area, with the M2 phenotype being beneficial to oligodendrogenesis [58]. Minocycline administered after ischemia provides protection to white matter, attenuating OPCs and myelin loss in the neonatal rat brain, even one week after treatment [59].

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