Among the cells that populate our brain there are also astrocytes which – as the name indicates – have the typical star shape. Although less well known than neurons, they are essential for neuronal activity and play a role in various pathologies of the nervous system. New research from the International Higher School of Advanced Studies (Sissa) shows that during embryonic development these same cells are produced differently in different areas of the brain. This information is very valuable because it reveals new mechanisms for regulating stem cells in the brain and could have therapeutic implications in the future. The research was led by Antonello Mallamaci of the International School of Advanced Studies (SISSA), and recently published in Cerebral Cortex.
How cells specialize
Astrocytes are a particular subpopulation of brain cells with a typical star shape. As with all other stem cells, even the neural ones, proceeding in embryonic development, gradually specialize to produce only some particular types of other cells; that is, they give rise to commissioned progenitors, capable in turn of multiplying and differentiating – for example – only in astrocytes or only in neurons. Until now, however, the hypothesis that in different areas of the brain this process could take place following different dynamics had never been investigated. “We imagined that there must be a discrepancy because the stem cells that go to form the hippocampus, a relatively small structure, are proportionally more numerous than those that go to form the neocortex, a larger structure, but no one had ever investigated the mechanism which is at the base ”, he explains Manuela Santoone of the first two authors of the study.
Research
The research team, using the mouse as an animal model, experimentally observed that stem cells from specific regions of the cortex have a different propensity to produce astrocytes, following two very specific dynamics. In the hippocampal area, and in the medial territories more generally, the neural stem cells produce a large number of progenitors that proliferate little and that after a short time differentiate into astrocytes. On the contrary, in the anterolateral zones of the cortex, the commissioned progenitors produced by the stem cells are few and differentiate into astrocytes relatively late, after having proliferated a lot.
The process of asthrogenesis
A dynamic that was under everyone’s nose, but that had remained unexplored before. Underlying this difference is an early exposure of stem cells to high doses of the transcription factor Emx2, which was already known to be involved in asthrogenesis. The Emx2 gene is, in fact, expressed at very high levels in the hippocampus area, right there where astrocytes are produced earlier than in other areas of the cerebral cortex. “One of the most interesting things we found is that hippocampal stem cells not only know they have to produce more commissioned progenitors, but are even able to program the behavior of daughter cells, in molecular terms, teaching them to proliferate less,” he explains. Laura Rigoldianother first author of the study resulting from a collaboration between Italian and US researchers.
Reproduce the behavior in vitro
The research team has verified that this behavior can be reproduced in vitro by forcing a neurostaminal cell to express the Emx2 gene as it occurs in the hippocampus: this signal is enough to induce the production of many progenitors commissioned with a short proliferation program, even in daughter cells. . “This study, focused on astrogenesis, further extends the list of mechanisms in which this key developmental gene is involved. Furthermore, it opens up interesting opportunities for new research projects focused on the study of the regional specialization of astrocytes, ”he says Manuela Santo.
Possible implications for glioblastoma
But that’s not all because the results of the study, in the future, could also have possible therapeutic implications for glioblastomas, very aggressive tumors that affect the brain. “At the moment it is still a speculation, so we are very cautious, but from other studies we conducted in the past we know that if we let the Emx2 gene express in tumor stem cells we greatly reduce its ability to grow” explains Mallamaci who adds : “This is because if the gene is highly expressed in neurostaminals, the cells ‘tell’ their daughter cells to proliferate less, and education is also passed on to subsequent generations.” Therefore, it seems that the tumor behaves like a ‘pathological caricature’ of what happens in nature: the same mechanisms that we have observed in this study could explain the functioning of those attempts at experimental therapy.