Astrocytes, the guardians of neuronal functions, appear to have a more significant role in brain evolution than previously thought. The team led by Professor Aleksandra Pękowska, head of the Dioscuri Centre for Chromatin Biology and Epigenomics at the Nencki Institute of Experimental Biology in Warsaw, reveals new genes and mechanisms contributing to this process. The group's work has just been published in Cell Stem Cell.

Astrocytes, in contrast to neurons, do not conduct electrical signals - they have a different task. They form the blood-brain barrier and maintain the correct environment of the brain parenchyma by, among others, regulating pH or ion concentration. Furthermore, astrocytes supply neurons with nutrients and remove metabolic waste products. In addition, astrocytes help control the formation and removal of synapses and provide the substances necessary for producing neurotransmitters, which are crucial for neuronal activity.  - They can, therefore, be called the guardians of the brain. There is virtually no neurological disease associated with astrocyte biology disturbances - says Prof Pękowska.

Previous studies revealed striking differences in mouse, monkey, and human astrocyte morphology. Human cells are the largest and most complex compared to other species, suggesting possible evolutionary changes in Astrocyte function (Figure 1). While revealing, past work has been primarily descriptive and focused on astrocytes from mature individuals. However, the fetal period of human life is not only a critical time for brain development, but it also molds future brain functions—many genes known to affect cognition are already or exclusively active at this stage.

This is why we focused on fetal astrocytes - explains Prof Pękowska. We obtained them using induced-pluripotent stem cells. Using transcriptomics, a whole-genome approach, we discovered that a very high percentage of genes that are more active in human than in chimpanzee or macaque astrocytes may be involved in the formation of extracellular vesicles (EV). According to these predictions, we found that human astrocytes produce more EVs than chimpanzee and macaque cells - says Prof Pękowska.

EVs are microscopic biological structures released by living cells into the extracellular space. They are present in all body fluids. EVs do not replicate but provide means for intercellular communication and can carry a variety of molecules, such as proteins, lipids, DNA, or RNA. EVs appear essential for the proper development of neurons.

Since the effect of EVs on astrocytes is poorly understood, we decided to test how vesicles secreted by human astrocytes affect macaque cells, says the researcher. It turned out that the monkey cells became larger and more complex under the influence of the human EVs. - This means that the particles have transferred some information potentially contributing to the evolution of the morphology (appearance) of the astrocytes.  But the mechanism underlying this phenomenon remains unclear, Prof Pękowska points out.

The study also found that genes associated with brain diseases are more often 'silenced' than 'activated' in human astrocytes compared to the cells of our ape-like relatives. The silencing of the disease-related genes provides our brain with additional functions. - We do not yet know what these functions are, but gaining them is so valuable that our species is willing to pay a high price - the reduced ability to buffer any changes that lead to further reduction in the activity of these genes. What evolutionary advantage does reducing the activity of genes associated with brain disease give us? This is now the focus of our research,' says Prof Pękowska.

In collaboration with Prof Bartosz Wilczyński, from the University of Warsaw, the team combined molecular biology and computational tools including artificial intelligence to address how the genetic differences between humans and chimpanzees relate to changes in gene expression between our two species. They found that evolutionary gene activation is linked to well-defined alterations in the DNA sequence.

Scientists at the Nencki Institute are just beginning their research regarding the role of astrocyte in brain evolution and the development of cognitive functions. The platform they have developed for acquiring primate astrocytes, reported in the publication, opens many possibilities for further analyses.