Scientists have discovered a hidden mechanism for repairing brain cells

Scientists have discovered a mechanism in adult mice that allows the network of astrocytes to be restored after the local destruction of these cells. The preserved astrocytes divided, sent long appendages to the damaged area, and then moved the nuclei of daughter cells along them. As a result, the empty area was repopulated with astrocytes within a few weeks. The results of the work of an international group of researchers were published in the journal Nature Neuroscience.

What are astrocytes?

Previously, it was believed that the adult brain is not able to fully restore the network of astrocytes after their mass death. In injuries and strokes, the preserved cells usually accumulate on the border of the damaged area and form a glial barrier, but do not populate its interior.

Astrocytes also become a target in disorders of the spectrum of opticoneuromyelitis, a rare group of autoimmune diseases of the central nervous system. In patients, the immune system produces antibodies against the protein aquaporin-4, which is located mainly on the surface of astrocytes.

How the research was conducted

A team led by Bruno Weber, a professor at the University of Zurich, created small areas in the somatosensory cortex of adult mice with selectively destroyed astrocytes.

To do this, the researchers used antibodies to aquaporin-4 and components of the complement system. This model reproduces some cellular processes that occur in disorders of the spectrum of opticoneuromyelitis.

The damaged areas had a diameter of less than 0.5 mm. Unlike a normal injury or stroke, the effects were mainly directed at astrocytes. The scientists did not reveal a noticeable violation of the vascular structure, blood flow, or the disappearance of neurons inside the study area.

Tissue repair was monitored for 60 days using two-photon microscopy. This method made it possible to repeatedly study the same part of the brain of living mice and monitor the behavior of individual cells. Additionally, the scientists used spatial transcriptomics to determine which genes were activated in astrocytes at different stages of recovery.

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How astrocytes repaired a damaged network

After the cells were destroyed, the astrocytes located at the edges of the damaged area began to change shape. They enlarged their appendages and directed them to the center of the empty area. The most pronounced elongation of the appendages was observed approximately on the fifth day after the injury. At the same time, calcium activity in the cells temporarily increased due to the restructuring of their structure.

Then the astrocytes began to divide. Within 60 days, about 60% of the cells located at the edges of the damaged area participated in this process. Approximately 1% of astrocytes divided in the control areas. Some mother cells formed up to four daughter cells.

However, the daughter cells did not immediately separate and moved independently to the damaged area. After division, the astrocytes remained multicellular for some time. The new nuclei advanced to the center of the lesion inside the long processes that shared a common cytoplasm with the mother cell.

This process of nuclear displacement is called nucleokinesis. About 75% of the nuclei studied changed position during the first week. More than 60% of them moved away from the mother cell at a distance of more than 30 microns.

Subsequently, the daughter cells became independent and occupied previously empty areas. The astrocyte network was gradually restored, and the damage-related gene activity returned to its normal state.

Why did the nuclei move separately from the cells

The researchers found that astrocytes did not use the usual migration of whole cells, but a sequential restructuring of their own structure.

First, the cell extended the process towards the damaged area, then divided the nucleus and conducted one of the new nuclei through the common cytoplasm. After that, an independent daughter cell was formed in a new place.

In this way, the astrocytes could be re-distributed over the damaged area without leaving its borders in the usual way. Previously, such behavior of mature cells of the cerebral cortex could not be traced in detail in living animals for several weeks.

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What did the recovery depend on?

The severity of the reaction depended on the area of damage. The destruction of a single cell or a small group of astrocytes almost did not trigger the recovery mechanism. With a larger local loss of cells, the division and movement of nuclei occurred much more actively.

According to scientists, the cause may be a violation of contact braking. In healthy tissue, astrocytes occupy separate areas and limit the growth of neighboring cells. When a large area is released, the disappearance of contacts can serve as a signal for division and restructuring.

Spatial analysis also revealed the temporal activation of genes associated with cell repair, shape change, and cytoskeleton organization. By day 17, many of these molecular changes had weakened as the damaged area filled in.

Does the mechanism work after a stroke

The authors separately checked whether the same process is observed in stroke. To do this, damage foci of comparable size were created in mice by cutting off the blood supply to a small area of the cortex.

The astrocytes near the hearth also divided, but there was no full-fledged colonization of the damaged area. The movement of nuclei was detected only in 17.6% of dividing cells, and it occurred over short distances.

A glial barrier formed around the stroke area, which limited the penetration of astrocytes into the damaged tissue. Thus, one cell division was not enough to restore the network.

This result shows that the discovered mechanism does not work in all types of brain damage. Its effectiveness is influenced by the condition of the surrounding tissue, the safety of blood vessels, the presence of dead neurons and the formation of a glial barrier.

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Has such a mechanism been found in humans?

The main experiments were conducted on mice. To test the possible connection of the results with human diseases, the scientists examined brain tissue samples from seven patients with optic neuromyelitis spectrum disorders.

Multinucleated astrocytes, elongated appendages, and signs of cell division were found in the damaged and adjacent areas. Such features were more common than in intact tissue.

Observations show that human astrocytes can enter a state similar to that found in mice. However, the analysis of postmortem and biopsy samples did not allow to trace the movement of nuclei in real time or to prove the complete restoration of the cellular network in patients.

Will the discovery help to restore the brain

The researchers identified genes and signaling pathways that were temporarily activated during astrocyte division, process elongation, and nuclear displacement. In the future, they may become targets for drugs that enhance the regenerative response of cells.

Theoretically, the management of these mechanisms can help restore the astrocyte network in diseases accompanied by selective loss of such cells. First of all, we are talking about disorders of the spectrum of optic neuromyelitis and some other astrocytopathies.

However, the work does not prove that the adult brain is able to fully recover after a stroke, traumatic brain injury, or neurodegenerative disease. The scientists did not study the formation of new neurons, but the return of astrocytes to a locally liberated area.

Before using the discovery to treat humans, it is necessary to determine which signals trigger the repair reaction, how functional new cells become, and whether it is safe to activate this process without excessive division and inflammation.