Activation and Role of Astrocytes in Ischemic Stroke

Abstract

Ischemic stroke refers to the disorder of blood supply of local brain tissue caused by various reasons. It has high morbidity and mortality worldwide. Astrocytes are the most abundant glial cells in the central nervous system (CNS). They are responsible for the homeostasis, nutrition, and protection of the CNS and play an essential role in many nervous system diseases' physiological and pathological processes. After stroke injury, astrocytes are activated and play a protective role through the heterogeneous and gradual changes of their gene expression, morphology, proliferation, and function, that is, reactive astrocytes. However, the position of reactive astrocytes has always been a controversial topic. Many studies have shown that reactive astrocytes are a double-edged sword with both beneficial and harmful effects. It is worth noting that their different spatial and temporal expression determines astrocytes' various functions. Here, we comprehensively review the different roles and mechanisms of astrocytes after ischemic stroke. In addition, the intracellular mechanism of astrocyte activation has also been involved. More importantly, due to the complex cascade reaction and action mechanism after ischemic stroke, the role of astrocytes is still difficult to define. Still, there is no doubt that astrocytes are one of the critical factors mediating the deterioration or improvement of ischemic stroke.

Keywords: astrocyte; blood–brain barrier; cerebral edema; glutamate; inflammation; ischemic stroke; oxidative stress.

FIGURE 1

Differences of astrocytes in different extent of injury. (A) Astrocytes in the resting state. Not all astrocytes express detectable levels of GFAP (Two cells in the middle of A). There are clear and definite boundaries between cells. Little or no proliferation. (B) Most astrocytes express detectable levels of GFAP when the injury occurs. The astrocyte soma swells and proliferation begins to appear (The cells with red nuclei represent proliferating astrocytes). (C) Swollen astrocytes start proliferating massively. The boundaries between cells are destroyed.

FIGURE 2

The intracellular mechanisms related to astrocyte activation. After ischemic stroke, different types of cells promote astrocyte activation by secreting various factors, including activated microglia, dead neurons, endothelial cells, and other cells. These factors act by entering the cell via multiple pathways, such as the JAK/STAT3 pathway, the Olig2 pathway, TGF-β/The Smad pathway, and other pathways.

FIGURE 3

Schematic representation of the significant constituent structures of the blood–brain barrier (BBB). The BBB is a complex composed of astrocyte endfoot, vascular endothelial cells, tight junction, basement membrane, and pericytes. The astrocytes regulate the homeostasis and function of BBB mainly by transporting different derived factors through their endfoot.