The CNS Wound

Stroke causes an area of damage and cell death, which is circumscribed by cellular barriers. Changes in extracellular matrix and cell adhesion molecules further surround the stroke site and set up barriers to the expansion of the stroke, and later provide a component of wound healing in the brain. The nature of tissue repair versus scar formation in the CNS was thought to involve mostly the “glial scar”: astrocytes that become reactive after injury, wall off the injury site, such as the stroke core, and deposit extracellular matrix proteins that further wall off the stroke, such as chondroitin sulfate proteoglycans. However, emerging data indicates that this centuries-old concept of the glial scar is not accurate. Reactive astrocytes form an important tissue barrier after stroke, and prevent systemic inflammatory cells that enter the stroke core from also invading adjacent and intact brain. However, this zone of reactive astrocytes may not be the source of fibrotic scar. In spinal cord injury and other CNS injuries, axons grow within zones of reactive astrocytes. These cells are not the inhibitory sources of axonal growth cone collapse and prevention of axonal sprouting that were previously considered. Instead, tissue fibrosis in the brain may arise from perivascular fibroblasts or pericytes.

In the Carmichael lab, several projects study the cellular and molecular mechanisms of tissue barrier formation and tissue fibrosis in the CNS scare. In one project, the heterogeneity of reactive astrocytes is under study to determine the distinct molecular systems that are active in cortical and white matter stroke and in astrocytes that are bordering the stroke vs some distance away. The goal is to understand how astrocytes form tissue barriers, what the function is of astrocytes further away from the stroke but still reactive and how these cells influence the main functions of repairing brain, such as angiogenesis, axonal sprouting and cellular responses in the oligodendrocyte lineage (oligodendrocyte precursor cells in particular). As part of this project, Dr. Amy Gleichman in the lab developed a new toolbox for more selectively labeling astrocytes. Astrocytes participate in more thn just forming tissue barriers, and studies in the lab are examining astrocyte interactions with blood vessels, synapses and other glial cells after stroke. A second project is looking at pericytes in their responses to stroke, specifically if these cells lead to aspects of tissue fibrosis.

In the above photo: white is a virally labeled astrocyte, red is an immunofluorescent stain for the endothelial cell and green is a stain for the astrocyte protein aquaporin 4.