Real-time imaging illuminates the coordination of neuronal stem cell activation

In all adult vertebrates, neuronal stem cells can be recruited to produce new neurons in the brain. However, little is known about these so-called “activation” processes.

Scientists from the Pasteur Institute, CNRS and Tel Aviv University, working in collaboration with École Polytechnic and INRAE, successfully performed 3D visualization and analysis of the spatial and temporal distribution of neuronal stem cell activation in the adult brain of zebra vertebrate models.

Their findings show for the first time that the activation events of these cells are coordinated in time and space. In particular, these results may help improve our understanding of the regulatory processes initiated during brain tumor formation. These findings were published in the April 5, 2021 issue of the journal Stem cells.

Stem cells, which are found in many adult vertebrate organs, including humans, are able to proliferate and differentiate to create new functional cells. For example, stem cells in the brain (neuronal stem cells) produce new neurons in adulthood. Most of the time, neuronal stem cells are in a state of rest known as “rest”. To produce neurons, they must first be activated and then split. This phase of activation is crucial: it is a prerequisite for the recruitment of stem cells, and it is also crucial for their survival (cells that are over-activated are quickly depleted) and for the position and type of neurons formed.

Within their niche, neuronal stem cells are activated and return to a state of rest in a random order and asynchronously, suggesting that these events can be coordinated at the cell population level. Scientists from the Zebra Neurogenetics Unit at the Pasteur Institute chose zebras to test this hypothesis because the adult zebra brain contains large amounts of neuronal stem cells, otherwise similar to mammalian stem cells.

Through intravital (noninvasive) two-photon imaging of adult fish, they were able to record stem cells in their niche for several weeks and study the activation pattern of each cell relative to neighboring cells in real time. Spatial statistical analysis and modeling performed in real time and in long-term computer simulations showed the existence of inhibitory interactions generated by activated cells, delaying the activation of other neighboring stem cells by several days.

Using an in vivo pharmacological molecule, the scientists also identified the involved molecular pathway, which is known as the Notch signaling pathway. Finally, they have shown that these interactions allow for the stable production of neurons in time and space.

“This is the first real-time and long-term imaging of an entire population of adult vertebrate neuronal stem cells. These findings show for the first time that neuronal stem cell activation events in vertebrate brain are time-coordinated and space within a niche,” commented Laure Bally-Cuif. CNRS scientist, lead author of the study, and head of the Zebra1 Neurogenetics Unit at the Pasteur Institute. Unexpectedly, this study also showed that stem cells themselves were involved in this coordination. Therefore, this research prompted the emergence of a new concept according to which stem cell populations self-organize as a dynamic system that allows spatial-temporal coordination of the behavior of each individual cell.

Such regulation can occur in tumor masses containing carcinogenic stem cells, in which stem cells have been observed in various states of rest or activation. It is also likely that such regulation takes place in stem cell populations in other adult organs where stem cells are located in compact niches, such as epithelium.

Connect a to a video showing stem cells covering one of the brain hemispheres of an adult fish. Stem cells were monitored for 23 days to analyze their positions, activation events, and differentiation. The fish were anesthetized and imaged with a two-photon microscope every 3 days. The dots show the center of each cell, and the arrows divide the stem cells: https: //www.youtube.com /to watch? v =bPZsMz5tsGM

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Journal reference:

Dray, N., and others. (2021) Dynamic spatio-temporal coordination of decisions about the fate of neuronal stem cells occurs through local feedback in the brain of adult vertebrates. Stem cells cells. doi.org/10.1016/j.stem.2021.03.014.

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