Sex differences in the induction and outcome of stroke

Many neurodegenerative diseases, as well as acute injuries such as strokes, are gender-specific. In multiple sclerosis (MS), one of the most common acquired diseases of the central nervous system in young adults, women predominate. The sex of patients influences many aspects of MS, including incidence, severity, activity, prognosis, comorbidities and treatment outcomes. In relation to stroke, it is known that women also have a higher mortality rate and poorer brain functionality compared to men. In stroke, this may be due in part to misdiagnosis leading to a delay in acute treatment or secondary prevention, similar to the diagnosis and treatment of heart attacks in men and women.
Microglia, first mentioned almost 100 years ago, are involved in the development and/or maintenance of most pathologies of the central nervous system and are therefore an important cell type to be investigated in all types of trauma or disease. Since their discovery, they have been considered a special type of brain cell because they migrate into the brain very early in development and are not formed there like neurons and macroglia. Microglia have many important functions in physiology as well as in acute and chronic pathology. Sex-specific differences in microglial gene expression and function have been found across the lifespan and play a key role in shaping brain function and behaviour. Sex hormone levels vary with age and sex. Microglia are able to respond directly and indirectly to changes in hormone levels by altering transcriptional gene expression, morphology and function.

In a recent study, we were able to show that reprogramming of oligodendrocytes can be induced after acute brain injuries with haemorrhage, even though they are terminally differentiated cells. By using different transgenic mouse lines with transient expression of fluorescent proteins or the Cre/LoxP system, we were able to show that these de-differentiated oligodendrocytes form a cell type that has both astroglial and oligodendroglial properties, hence we named these cells AO cells. We also confirmed that these AO cells are also present in wild-type mice by analysing RNA expression. Fate mapping by two-photon laser scanning microscopy (fluorescent reporter mice) or using the split/Cre system with astroglial and oligodendroglial expression of Cre fragments showed the bipotential fate of AO cells to differentiate into either oligodendroglia (oligodendrocytes and oligodendrocyte precursor cells) or astroglia. We could show that AO cells are induced by the cytokine interleukin-6 (IL-6), released by activated microglia after acute injury. In conclusion, our results emphasise the plastic potential of oligodendrocytes in acute brain trauma induced by microglia released, both after acute injury and after minor (disruption of the pial vessels) or major (occlusion of the middle cerebral artery) stroke.

Combining the findings that:

1. women have a higher mortality rate and poorer treatment outcomes than men in the event of a stroke,
2. in MS, a disease in which oligodendrocytes lose their function, women are also affected more frequently than men, and
3. microglia are the neuronal cell type that is most strongly influenced by gender,

raises the question of whether the induction of AO cells from oligodendrocytes is sex-dependent and thus whether the consequences of a stroke could differ due to a different number of AO cells after the primary injury.
A fundamental understanding of the gender-specific differences after minor but also major injuries (PVD, MCAO) will provide important insights into the pathophysiology with primary and secondary effects, the further course of the disease and possible treatment targets after acute trauma.