Oligodendrocyte degeneration and recovery after focal cerebral ischemia

Abstract

The vulnerability of oligodendrocytes to ischemic injury may contribute to functional loss in diseases of central white matter. Immunocytochemical methods to identify oligodendrocyte injury in experimental models rely on epitope availability, and fail to discriminate structural changes in oligodendrocyte morphology. We previously described the use of a lentiviral vector (LV) carrying eGFP under the myelin basic protein (MBP) promoter for selective visualization of oligodendrocyte cell bodies and processes. In this study, we used LV-MBP-eGFP to label oligodendrocytes in rat cerebral white matter prior to transient focal cerebral ischemia, and examined oligodendrocyte injury 24 hours, 48 hours and one week post-reperfusion by quantifying cell survival and assaying the integrity of myelin processes. There was progressive loss of GFP+ oligodendrocytes in ischemic white matter at 24 and 48 hrs. Surviving GFP+ cells had non-pyknotic nuclear morphology and were TUNEL-negative, but there was marked fragmentation of myelin processes as early as 24 hours after stroke. One week after stroke, we observed a restoration of GFP+ oligodendrocytes in ischemic white matter, reflected both by cell counts and by structural integrity of myelin processes. Proliferating cells were not the main source of GFP+ oligodendrocytes, as revealed by BrdU incorporation. These observations identify novel transient structural changes in oligodendrocyte cell bodies and myelinating processes, which may have consequences for white matter function after stroke.

Erythropoietin (EPO) Increases Myelin Gene Expression in CG4 Oligodendrocyte Cells through the Classical EPO Receptor

“…This might be relevant to demyelinating diseases, and it is interesting to note that EPO is effective not only in animal models of MS but also in a pilot clinical trial (36). Furthermore, induction of myelin genes, together with promotion of oligodendrogenesis, might play a role in EPO-induced neurological recovery in stroke as well as in neonatal hypoxic-ischemic brain injury, where oligodendrocyte damage is an important pathogenic component (5,(37)(38)(39).…”

Nogo receptor blockade overcomes remyelination failure after white matter stroke and stimulates functional recovery in aged mice

“…Unlike MS, stroke kills all cell types within the white matter and creates a microenvironment that is different from the immune-mediated pathology. Initial studies in this field indicate that OLs undergo a profound morphological change after large artery stroke (12). However, whether OPCs can migrate to areas of injury, differentiate into OLs, and partially repair the ischemic lesion remain to be described.…”

Models That Matter: White Matter Stroke Models

“…The induction of the reactive state of OPCs in demyelinating injury involves specific inflammatory cytokines, such as bone morphogenic protein (BMP)-4 and the heparin-binding growth factor pleiotrophin, insulin-like growth factor signaling, notch signaling, and the transcription factors (i.e., Nkx2.2, Olig1, and Olig2) [65,67,68,70,71]. Oligodendrocytes undergo profound morphological changes after stroke that suggest dysfunction and recovery [72]. However, it is not known if these same molecular systems play a role in white matter stroke, which differ from models of demyelinating injury in critical aspects of the previously mentioned environmental cues (i.e., the nature of the inflammation, the involvement of hypoxic and free radical events, and the lack of a toxic oligodendrocyte cell death that is present in many of the demyelinating models).…”

“…Oligodendrocyte cell bodies can die and thus lose their ability to maintain myelin loops. Isolated loops of myelin can lose their energy source and retract [72]. Focal segments of axons deprived of ATP undergo a distinct molecular process leading to Wallerian degeneration (for more detail see Stirling and Stys [73]).…”

“…By 6 h after MCAO, myelin appears vacuolated and dissociated from the axolemma [77]. More recently, McIver et al [72] used the rat model of MCAO to show that oligodendrocytes die and retract processes within 24 h of stroke. They also demonstrated that 1 week after MCAO, oligodendrocytes repopulate and extend processes in areas of ischemic white matter affected by stroke.…”