This study reveals a feedback mechanism that maintains a balance between resting and activated stem cells in the brain, ensuring their preservation throughout life. In addition to deepening our understanding of how the brain works, these discoveries may open new doors for the development of treatments for neurodegenerative diseases and brain injuries.
The stem cells in our body live in a very dynamic environment, surrounded by many other cells and receiving different chemical signals. To keep tissues healthy and functioning properly, these cells alternate between a resting state (quiescence) and an active state, in which they begin to divide and generate new cells.
This balance is essential to prevent the wear and tear of stem cells throughout life and is regulated by both internal signals (from the cell itself) and external signals (from the surrounding environment).
In the adult brain, neural stem cells (NSCs) are located in a region called the subventricular zone (SVZ), where most of them remain in a resting state. When activated, these cells begin to divide and give rise to other intermediate cells called transient amplifying cells (TAPs), which in turn generate new neurons.
Proliferation and maturation of neural stem cells. Image adapted from Bischofberger J., 2007.
Neural stem cells are in direct contact with blood vessels and receive chemical signals from the fluid that fills the brain's ventricles.
In addition, they interact with other types of cells, such as astrocytes, microglial cells (which are part of the brain's immune system), and mature neurons. All of these elements form a complex environment, full of signals that control the behavior of neural stem cells.
One of these control mechanisms involves calcium (Ca²⁺), which acts as a signaling device within cells. Small variations in calcium levels can determine whether a stem cell remains dormant or becomes active and begins to divide. However, the details of how these cells interpret environmental signals and regulate their state have not yet been fully understood.
The image above shows an example of a neuronal movie created using calcium imaging. Source: Professor Dorit Hochbaum, UC Berkeley
In this study, researchers used advanced technology to directly observe changes in calcium levels in neural stem cells and identify which neighboring cells influence their activity.
They found that nearly all changes in calcium levels occur in parts of neural stem cells that are in direct contact with other cells in the environment. Using artificial intelligence, the scientists were able to predict which cell-to-cell interactions were linked to these changes in calcium.
The study revealed that transient amplifier cells, which are the direct descendants of neural stem cells, play a key role in regulating the very stem cells that generated them.
Transient amplifier cells send calcium signals to neural stem cells through specific points of contact. The researchers identified that this communication occurs through molecules called ephrins (EfnB1) and their receptors (EphB2). When transient amplifier cells release these molecules, neural stem cells remain in a resting state.
To confirm this finding, the scientists manipulated this system in different ways. When they eliminated the transient amplifier cells with a drug, the stem cells lost their control signals and began to activate more than normal.
On the other hand, when they artificially increased the activity of this system, the neural stem cells remained quiescent for longer.
These results show that the number of transient amplifier cells and their contact with the neural stem cells determines whether the stem cells remain quiescent or become active.
Human neural stem cells growing in culture. NSCs can be grown as floating 3D neurospheres (A) or attached 2D monolayers (B)
The more transient amplifier cells there are, the stronger the signal for the neural stem cells to remain inactive. If the number of transient amplifier cells drops or if communication between these cells is disrupted, the stem cells spring into action and begin to divide.
This study reveals a “feedback” mechanism that maintains the balance between quiescence and activation of stem cells in the brain, ensuring their preservation throughout life. In addition to deepening our understanding of how the brain works, these findings may open new doors for the development of treatments for neurodegenerative diseases and brain injuries.
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Neural stem cell quiescence and activation dynamics are regulated by feedback input from their progeny under homeostatic and regenerative conditions
Alina Marymonchyk, Raquel Rodriguez-Aller, Ashleigh Willis, Frédéric Beaupré, Sareen Warsi, Marina Snapyan, Valérie Clavet-Fournier, Flavie Lavoie-Cardinal, David R. Kaplan, Freda D. Miller, Armen Saghatelyan
Cell Stem Cell. 6 February 2025
Abstract:
Life-long maintenance of stem cells implies that feedback mechanisms from the niche regulate their quiescence/activation dynamics. Here, in the mouse adult subventricular neural stem cell (NSC) niche, we charted a precise spatiotemporal map of functional responses in NSCs induced by multiple niche cells and used machine learning to predict NSC interactions with specific niche cell types. We revealed a feedback mechanism whereby the NSC proliferative state is directly repressed by transient amplifying cells (TAPs), their rapidly dividing progeny. NSC processes wrap around TAPs and display hotspots of Ca2+ activity at their points of contact, mediated by ephrin (Efn) signaling. The modulation of Efn signaling or TAP ablation altered the Ca2+ signature of NSCs, leading to their activation. In vivo optogenetic modulation of Ca2+ dynamics abrogated NSC activation and prevented niche replenishment. Thus, TAP-to-NSC feedback signaling controls stem cell quiescence and activation, providing a mechanism to maintain stem cell pools throughout life.
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