Longitudinal intravital imaging of cerebral microinfarction reveals a dynamic astrocyte reaction leading to glial scar formation

Abstract

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown.Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3 kDa dextran (but not 2 MDa dextran) indicating microinfarction-related blood-brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.

Analysis of ischemic stroke-mediated effects on blood–brain barrier properties along the arteriovenous axis assessed by intravital two-photon imaging

“…Further insights into the cellular and molecular mechanisms underlying BBB breakdown, vascular regrowth or scar formation after an ischemic event, can be made utilizing the vast number of genetically modified mouse lines available. This includes mice with fluorescently labeled astrocytes, which have recently been employed to study the involvement of reactive astrocytes in revascularization and vascular plasticity after ischemic stroke by intravital two-photon imaging [ 20 , 42 ]. Moreover, conditional knockout or overexpressing mouse lines can be deployed to dissect the role certain proteins or signaling pathways play in BBB regulation during stroke progression.…”

Injectable Bombyx mori (B.mori) silk fibroin/MXene conductive hydrogel for electrically stimulating neural stem cells into neurons for treating brain damage

“…Glial scarring is an important factor that inhibits neuronal regeneration. 42 Therefore, overcoming the obstruction of glial scarring is important to promote neural regeneration and functional repair. As shown in Fig.…”

Injectable Bombyx mori (B. mori) silk fibroin/MXene conductive hydrogel for electrically stimulating neural stem cells into neurons for treating brain damage

“…5C and D. Glial scarring is an important factor that inhibits neuronal regeneration [51]. Therefore, overcoming the obstruction of glial scarring is important to promote neural regeneration and functional repair.…”