Oligodendrocyte Progenitor Cell Proliferation and Fate after White Matter Stroke in Juvenile and Adult Mice

Abstract

The incidence of stroke in children is 2.4 per 100,000 person-years and results in long-term motor and cognitive disability. In ischemic stroke, white matter (WM) is frequently injured, but is relatively understudied compared to grey matter injury. Previous research suggests that the cellular response to WM ischemic injury is different at different ages. Little is known about whether WM repair mechanisms differ in children and adults. We utilized a model of focal ischemic WM injury to determine the oligodendrocyte (OL) response to focal WM ischemic injury in juvenile and adult mice. Methods: Juvenile (21–25 days of age) versus adult (2–3 months of age) mice underwent stereotaxic injection of the potent vasoconstrictor N5-(1-iminoethyhl)-L-ornithine (L-NIO) into the lateral corpus callosum (CC). Animals were sacrificed on postoperative day 3 (acute) or 21 (chronic). Cell birth-dating was performed acutely after WM stroke with 5-ethynyl-2-deoxyuridine (EdU) injected intraperitoneally. Immunohistochemistry was performed, as well as stereology, to measure injury volume. The acute oligodendrocyte progenitor cell (OPC) proliferation and the chronic OL cell fate were determined with immunohistochemistry. Compound action potentials were measured in the CC at acute and chronic time points. Results: Acutely WM injury volume was smaller in juveniles. There was significantly greater OPC proliferation in juvenile animals (acute) compared to adults, but newly born OLs did not survive and mature into myelinating cells at chronic time points. In addition, juveniles did not have improved histological or functional recovery when compared to adults. Protecting newly born OPCs is a potential therapeutic target in children with ischemic stroke.

Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l-Arginine:Glycine Amidinotransferase Deficiency

“…Moreover, the loss of BCAS1 specifically induced hypomyelination and expression of inflammation-related genes in the brain [20]. In line with previous studies, we found increased Bcas1 levels after stroke which are likely to represent a compensatory mechanism of oligodendrocyte proliferation after hypoxia and energy deficiency [27]. Bcas1 levels were increased in AGAT -/-mice and correlate with cognitive impairment [19].…”

Electroacupuncture Inhibits Myelin Sheath Injury in the Internal Capsule After Focal Cerebral Infarction in Rats Through the Nogo-A/NgR Signaling Pathway

“…The repairability of CNS in the peri-infract area after stroke is limited. Dingman et al [ 42 ] found that focal WM stroke mice had a profound increase in oligodendrocyte progenitor cells 24 h after ischemia, which was sustained for up to 7 days, but these new cells did not survive to maturity after WM stroke. To further determine the protective effect of EA on myelin fibers in ischemic WM, we employed immunohistochemistry and western blot methods to detect the expression of Nogo-A and NgR.…”

Cannabinoids as Glial Cell Modulators in Ischemic Stroke: Implications for Neuroprotection

“…On the other hand, stroke induces a strong proliferative response of OPCs, which migrate to the affected area and mature into myelinating oligodendrocytes ( Figure 3B ) ( Zhang et al, 2011 ; Bonfanti et al, 2017 ). This proliferative response seems to be age-dependent ( Dingman et al, 2018 ). However, the proportion of the newly formed oligodendrocytes that reach a mature stage after stroke is surprisingly low ( Bonfanti et al, 2017 ; Dingman et al, 2018 ).…”

“…This proliferative response seems to be age-dependent ( Dingman et al, 2018 ). However, the proportion of the newly formed oligodendrocytes that reach a mature stage after stroke is surprisingly low ( Bonfanti et al, 2017 ; Dingman et al, 2018 ). The mechanisms of this developmental impairment are not yet clear, although excitotoxicity, inflammation, and oxidative stress seem to play a key role ( Figure 3B ).…”