Gliogenesis from the subventricular zone modulates the extracellular matrix at the glial scar after brain ischemia

Abstract

ABSTRACTActivation of the subventricular zone (SVZ) after cerebral ischemia is one of the early responses in the brain to counteract the loss of neurons and reduce tissue damage. Impaired brain regions communicate with the SVZ through many chemotactic messages that result in neural stem cells (NSC) migration and differentiation. However, the activation of gliogenesis and the role of newborn astrocytes in the post-ischemic scenario is still under debate. We have previously shown that adenosine release after brain ischemia prompts the SVZ to generate new astrocytes. Here, we use transient brain ischemia in mice to define the cellular origin of these astrocytes in the SVZ neurogenic niche and investigate their role in the pathological process. By combining immunofluorescence, BrdU-tracing and genetic cellular labelling, we tracked the migration of newborn astrocytes, positive for the proteoglycan marker Thbs4, from the dorsal and medial SVZ to the perilesional barrier surrounding the ischemic core, termed “glial scar”. We found that these Thbs4-positive astrocytes modulate the dense extracellular matrix at the lesion border by synthesis but also degradation of hyaluronan. We also show that while the accumulation of this polymer at the lesion is sufficient to recruit newborn astrocytes, its degradation at the SVZ correlates with gliogenesis. These results point to newborn astrocytes as a plausible pharmacological target to modulate the glial scar after brain ischemia and facilitate tissue regeneration.