Gliogenesis from the subventricular zone after brain ischemia.

Abstract

Brain stroke is the second cause of death worldwide. Among the cerebrovascular accidents, ischemic stroke is the most common. It is caused by an interruption of blood flow, and it is characterized by sudden neuronal death (necrosis in the core) and apoptotic neuronal loss in the penumbra. After the generation of the glial scar surrounding the penumbra, ischemia in animal model can activate the neurogenic machinery in the subventricular zone (SVZ). However, the rapid formation of the glial scar after brain ischemia represents a double edged sword for brain survival. On one side, the ischemic scar isolates the healthy tissues from deadly factors released in the ischemic core but on the other hand, it impedes the neuronal regeneration from the SVZ. Previous results in our laboratory demonstrated that high levels of extracellular adenosine, one of the factors released after brain ischemia, could activate theSVZ and generate new astrocytes. In this PhD project, we used a mice model of transient brain ischemia by middle cerebral artery occlusion (MCAO) to accomplish the following objectives:1) To characterize the SVZ activation and astrogliogenesis following brain ischemia;2) To investigate the role of newborn astrocytes generated from the SVZ.By combining immunofluorescence with genetic cellular tracing (in vivo electroporation of neural progenitor cells) we demonstrated that brain ischemia induced the generation of newborn astrocytes from the SVZ. Newborn astrocytes expressed the specific marker Thbs4 and were derived from the activated Type B cells at the dorsal SVZ. The neural stem cells and the Thbs4 astrocytes generated from the SVZ, deviated their physiological route to the olfactory bulb and reached the ischemic scar. Here, astrocytes generated after brain ischemia could degrade and synthetize the hyaluronic acid of the extracellular matrix suggesting a dual role in the modulation of the ischemic glial scar. We demonstrated for the first time that astrocytes derived from SVZ can produce, uptake and degrade the hyaluronic acid of the extracellular matrix. Our results can open a new pharmacological strategy to modulate the formation and the remodeling of the glial scar, facilitate the tissue regeneration after brain ischemia, and propose astroglia as a possible pharmacological target