The neurogenic potential of astrocytes : a story of transformation and renewal

Abstract

To not simply repair an organ, but to regenerate and fully recover its function, like there was no injury at all, that is the goal of regenerative medicine. Of all the organs in the human body, the most delicate and difficult to regenerate is the human brain. Our understanding of its physiology changed dramatically in the last decades and the concept of the human brain as a never-changing tissue, where neurons are lost, but not produced after development is no longer valid. Today we know that new neurons constantly form and re-shape the connections between each other and that even in the adult brain, there are populations of stem cells that generate new neurons. Nevertheless, after an injury, a recovery ad initio is not possible in the adult human brain.

Different approaches have been tried to change this inability of the brain to regenerate. Stem cells have been the main target for the majority of these strategies, either by stimulating stem cells, which reside in the brain, or by retrieving them from outside sources. The problem with the endogenous stem cells is that, in the adult brain, they are not very active and can generate a very limited number of new neurons, which are insufficient for the recovery of the damaged tissue. As for the external sources of stem cells, these are not always available and they may involve problems of graft rejection. Therefore this is the reason for looking at alternative options within the brain itself.

Astrocytes are one of the most represented cell types in the adult mammalian brain, they can be easily generated and are strikingly similar to the stem cells. Astrocytes have been observed to generate neurons in animal models of Huntington’s disease and stroke. Notch signaling seems to be crucial in regulating the neurogenic ability of astrocytes. In animal models where Notch signaling is impaired by deletion of Rbpj, astrocyte-derived neurons and neurogenic cells can be identified within the striatum. But many questions are still open: what processes are necessary for the astrocytes to generate neurons? Why do astrocytes from the striatum generate neurons, while astrocytes in other brain regions do not? Can we harness this neurogenic potential and use it in regenerative medicine? If so, how? These are some of the questions I tried to answer with my work.

In Paper I, we combined the two models we have previously described to induce astrocytederived neurogenesis. We blocked Notch signaling specifically in astrocytes by using an animal model in which Rbpj is knocked-out in Cx30-expressing cells. Subsequently, we induced a stroke in the same animals. After seven weeks, we observed an increase in the number of neuroblasts derived from astrocytes, compared to the deletion of Rbpj or stroke alone. This study shows that astrocyte-derived neurogenesis is a complex process, which can be induced by different kinds of stimuli, and further enhanced by their interplay.

In Paper II, we decided to further investigate what happens in astrocytes, on a transcriptomic level, when they become neurogenic. We used single-cell RNA sequencing to identify the differences between neurogenic and non-neurognic astrocytes at different time-points. We observed that, during differentiation into neurons, striatal astrocytes follow a trajectory that is reminiscent of the one followed by stem cells of the subventricular zone. Moreover, they start to sense the environment for pro-neurogenic factors. One of this is Egf, which administration in the brain of Rbpj-deleted mice enhances astrocytes-derived neurogenesis. Remarkably, the effect of Egf is visible even in areas of the striatum where astrocytes do not respond in the absence of injury.