Healing the Brain: Scientists Discover a Mechanism of Neural Regrowth in Stroke Survivors

Li, Wenlu, et al. “Endothelial cells regulate astrocyte to neural progenitor cell trans-differentiation in a mouse model of stroke.” Nature Communications, vol. 13, no. 7812, 2022. https://doi.org/10.1038/s41467-022-35498-6.

A stroke results when a blood vessel in the brain is either ruptured or blocked by a blood clot or fatty deposits (atherosclerosis). This greatly reduces the supply of oxygen and nutrients to nearby brain cells. As the neurons are damaged and destroyed, the stroke victim begins to exhibit symptoms such as weakness, slurred speech, and facial droop. The extent of brain damage that a stroke victim will experience varies, depending on the location and type of stroke and the time that the victim receives medical attention.

Brain damage from a stroke heals slowly, and stroke survivors frequently have permanent neurological deficits (such as paralysis or amnesia). The conducting neurons of the brain are unable to undergo mitosis and thus cannot divide to replace lost tissue. Fortunately, neuroplasticity allows the brain to gradually repair some of the damage and recover some of its lost functions. Neuroscientists are greatly interested in learning more about how the brain heals itself, as this may lead to the development of new treatments that can improve outcomes for stroke patients.

Recently, a team of researchers investigating stroke physiology discovered a mechanism by which the brain replaces lost and damaged tissue. They combined cultures of astrocytes (a type of non-conducting neuron responsible for supporting the brain’s conducting neurons) with endothelial cells (which constitute the blood-brain barrier), conducting neurons, and pericytes. After depriving these cultures of oxygen and glucose for three hours to mimic the effects of a stroke, they observed the changes that occurred among the cells.

They discovered that endothelial cells play a significant role in replacing dead neurons. Since endothelial cells are in direct contact with the cerebral blood vessels, they are highly sensitive to changes in the amounts of oxygen and nutrients being carried to brain tissue. The researchers found that when endothelial cells were deprived of oxygen and glucose, they released a protein called Ascl1. This protein caused astrocytes to become neural progenitor cells. Neural progenitors, unlike conducting neurons, can undergo mitosis to create new conducting neurons. This mechanism replaces some of the tissue damaged by the stroke.

Figure 1. When an artery has been occluded, nearby endothelial cells release vesicles containing Ascl1, which are taken up by astrocytes.

Figure 2. Astrocytes that take up Ascl1 turn into neural progenitor cells, which subsequently divide into new conducting neurons.

After demonstrating this phenomenon in vitro, the researchers wanted to determine if it could also occur in vivo. First, they induced stroke-like conditions in mice by surgically tying off one of their cerebral arteries. They then performed biochemical analyses on mouse brains that were humanely removed 1, 2, 3, and 7 days after the induced stroke. The results of these analyses demonstrated that Ascl1 is expressed by brain endothelial cells after a stroke and is subsequently taken up by astrocytes.

To test whether this phenomenon has therapeutic potential, the researchers induced strokes in another group of mice and caused their endothelial cells to overexpress Ascl1. This resulted in increased rates of neurogenesis, hastening the repair of the damaged areas in the mice’s brains. While the expression of Ascl1 in human stroke victims has not yet been studied, it is possible that this phenomenon may in the future be exploited to improve outcomes for human patients.