Ferroptosis in oligodendrocyte progenitor cells mediates white matter injury after hemorrhagic stroke

Abstract

Oligodendrocyte progenitor cells (OPCs) differentiate to myelin-producing mature oligodendrocytes and enwrap growing or demyelinated axons during development and post central nervous diseases. Failure of remyelination owing to cell death or undifferentiation of OPCs contributes to severe neurologic deficits and motor dysfunction. However, how to prevent the cell death of OPCs is still poorly understood, especially in hemorrhagic diseases. In the current study, we injected autologous blood into the mouse lateral ventricular to study the hemorrhage-induced OPC cell death in vivo. The integrity of the myelin sheath of the corpus callosum was disrupted post intraventricular hemorrhage (IVH) assessed by using magnetic resonance imaging, immunostaining, and transmission electron microscopy. Consistent with the severe demethylation, we observed massive cell death of oligodendrocyte lineages in the periventricular area. In addition, we found that ferroptosis is the major cell death form in Hemin-induced OPC death by using RNA-seq analysis, and the mechanism was glutathione peroxidase 4 activity reduction-resulted lipid peroxide accumulation. Furthermore, inhibition of ferroptosis rescued OPC cell death in vitro, and in vivo attenuated IVH-induced white matter injury and promoted recovery of neurological function. These data demonstrate that ferroptosis is an essential form of OPC cell death in hemorrhagic stroke, and rescuing ferroptotic OPCs could serve as a therapeutic target for stroke and related diseases.

Iron homeostasis imbalance and ferroptosis in brain diseases

“…In recent years, the mechanism of the iron homeostasis imbalance represented by ferroptosis in the progression of neurodegenerative diseases has been supported by increasing amounts of evidence. Ferroptosis, characterized by altered brain iron homeostasis, dysregulation of the antioxidant system, and oxidative damage, plays an important role in the progression of neurodegenerative diseases such as stroke, AD, PD, and so on 116,219–226 . Therefore, elucidating the mechanisms involved in ferroptosis is crucial for the treatment of neurodegeneration.…”

“…114 Combined with recent research that hemoglobin causes damage to mitochondrial function in primary cultured OPCs, inhibits OPCs proliferation, and even cell death, it should be emphasized the importance of protecting OPCs against cell death after stroke to reduce brain injury and promote recovery. 115,116 Therefore, controlling the response of neurogliocytes, like the phenotype switch of microglia, the expression of inflammatory mediators like LCN2, and protecting OPCs might provide attractive therapeutic targets for stroke. However, it also should be noted that though M1 microglia might increase inflammation levels in the brain, the long-term and improper inhibition of the M1 microglia might cause an adverse effect on the phagocytosis to iron and other fragments, thus leading to the deterioration of neurological function.…”

Elucidating the progress and impact of ferroptosis in hemorrhagic stroke

“… Li et al (2018) used TEM to observe mitochondria characteristics of ferroptosis in axons of oligodendrocytes. Subsequently, they further systematically presented ample evidence of ferroptosis in oligodendrocytes after ICH ( Shen et al, 2022 ). Dexpramipexole has also been reported to attenuate white matter damage caused by oligodendrocyte ferroptosis in mice after ICH, thereby improving spatial localization and motor function ( Wang B. et al, 2022 ).…”

Ferroptosis and central nervous system demyelinating diseases

“…The main causes of severe demyelination of white matter in mice after intraventricular hemorrhage (IVH)are periventricular iron deposition and oligodendrocyte death. Hemin, a hemoglobin degradation product, reduces the expression and activity of GPX4 in oligodendrocytes, and induces ferroptosis (Baldacchino et al, 2022; Shen et al, 2022). In addition, Fer‐1, an ferroptosis inhibitor, can reduce oxidative stress oligodendrocytes in vitro and prevent ferroptosis, thereby improving the integrity of myelin sheath after IVH (Shen et al, 2022).…”