Researchers have shown that two proteins prevent the formation of scars in the brain, thereby enhancing the ability of tissue to regenerate
While cells are renewed regularly in most tissues, the number of nerve cells in the human brain and spinal cord remains constant . Although nerve cells can regenerate in the brain of adult mammals, as Professor Magdalena Götz, a scientist at Ludwig-Maximilians-Universitaet (LMU), Munich , has previously shown, young neurons from brain-injured patients are unable to integrate into existing neural networks and to survive. This appears to be due to glial cells, which make up the supporting tissue of the brain. The microglia, in particular, triggers inflammation and causes scars that isolate the injured site from the healthy brain, but in the long run prevent the correct incorporation of new neurons into the circuits. How the body regulates these mechanisms was previously unknown.
Now, a team led by LMU cell biologist Prof. Jovica Ninkovic has shown that reducing the reactivity of microglia is crucial for preventing chronic inflammation and tissue scarring in order to improve regeneration capacity.
For the study, experiments were carried out on zebrafish. Unlike mammals, the central nervous system (CNS) of zebrafish has exceptional regenerative power . In the event of injury, neural stem cells generate, among other responses, long-lived neurons. Furthermore, in these fish, lesions to the central nervous system result in only transient glial cell reactivity, which facilitates the integration of nerve cells into injured regions of the tissue. “The idea was to identify the differences between zebrafish and mammals to understand which signaling pathways in the human brain inhibit regeneration and how we could intervene,” explains Ninkovic.
Zebrafish help research
Scientists willfully inflicted injury to the central nervous system of animals, causing microglia to activate. At the same time, the researchers found an accumulation of TDP-43 lipid droplets in the lesions. To date, the TDP-43 protein has been associated primarily with neurodegenerative diseases. Granulin
also played an important role in zebrafish. This protein contributed to the removalof the TDP-43 protein. Following the removal of TDP-43, microglia transitioned from the activated to the resting form. The result was unhealed regeneration of the lesion. Granulin deficiency has also been induced experimentally, and has shown poor regeneration of the lesion, with scientists suspecting that granulin plays an important role in nerve regeneration in zebrafish.
To explore the comparison between humans and zebrafish, Ninkovic’s team analyzed material from patients who died of brain injuries. Again, a correlation was found between the degree of microglial activation and the accumulation of lipid droplets and TDP-43 condensates. The corresponding signaling pathways in human tissue were therefore comparable to those in zebrafish.
The LMU researcher sees “ potential for new therapeutic applications in humans”. The next step will be to test whether the known low molecular weight compounds are suitable for inhibiting microglial activation signaling pathways, thus promoting the healing of neural lesions.
- TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury. (nature.com)