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Researchers Discover the Key to Awakening Dormant Neural Stem Cells

A recent paper published in Science Advances sheds light on the metabolic features of neural stem/progenitor cells (NSPCs). The researchers from the Universities of Geneva (UNIGE) and Lausanne (UNIL) found that NSPCs in a quiescent state have high levels of mitochondrial fatty acid β-oxidation, which might play a more important role in NSPC quiescence than previously anticipated.

NSPCs reside in the adult brain and have the ability to self-renew and generate new neurons throughout life. Consequently, NSPCs hold great promise for therapeutic applications in regenerative medicine and have the potential to provide new treatments for a wide range of neurological disorders. However, much remains to be learned about their behaviour and regulatory mechanisms.

What do we know about neural stem cells?

To sustain lifelong tissue regeneration and maintenance, NSPCs must maintain a tight balance between quiescence, proliferation, and differentiation into the various specialized cells that make up the brain. While they primarily remain inactive in adulthood, they can multiply and transform into other cells when they receive certain signals. These signals can come from within the cells or from outside factors, like changes in the environment.

The underlying mechanisms of NSPC activation are not fully understood, but recent studies have shown that cellular metabolism plays a critical role in determining the activity state of stem cells. However, the metabolic processes that regulate the behaviour of neural stem cells are very complex. Notably, it appears that their metabolism plays an important role in determining whether they remain inactive or start to multiply and differentiate.

The metabolism of neural stem cells is similar to that of other types of stem cells in the body. They produce energy primarily through a process called glycolysis. However, when they start to differentiate, their metabolism shifts toward oxidative metabolism, which helps create energy to fuel the specialized functions of mature cells. Recent studies suggest that mitochondrial metabolism might play a more important role for NSPC quiescence than previously anticipated. One key factor is the mitochondrial pyruvate carrier (MPC), which helps transport energy-producing molecules into the mitochondria.

Wake up stem cells!

The researchers decided to investigate whether disruption of pyruvate import into mitochondria by inhibiting the MPC would affect NSPC maintenance, activation, and differentiation. The study utilized pharmacological MPC inhibition and genetic deletion of Mpc1 to inhibit the MPC, and used single-cell RNA sequencing and metabolic analyses to assess its impact on NSPC behaviour.

They found that quiescent NSPCs express high levels of MPC and require pyruvate import into mitochondria for the maintenance of quiescence. Inhibition of MPC triggered their activation by increasing the intracellular pool of aspartate despite a substantial decrease of TCA cycle intermediates. Furthermore, conditional MPC1-knockout NSPCs were able to differentiate into mature neurons, indicating high metabolic flexibility, allowing NSPCs to adapt their metabolism according to substrate availability. The increased activation and undisturbed differentiation of MPC1-cKO NSPCs led to an overall increase in neurogenesis in adult and middle-aged mice. In other words, the activation of dormant NSPCs resulted in the generation of new neurons in the brains of adult and even aged mice.

The study’s findings shed new light on the role of cell metabolism in the regulation of neurogenesis, and thus allow researchers to wake up dormant neural stem cells by modifying their mitochondrial metabolism. “With this work, we show that redirection of metabolic pathways can directly influence the activity state of adult NSCs and consequently the number of new neurons generated,” said Professor Knobloch, co-lead author of the study. These findings have significant implications for the future of regenerative medicine and the treatment of neurological disorders, as Jean-Claude Martinou, co-lead author of the study said; “These results shed new light on the role of cell metabolism in the regulation of neurogenesis. In the long term, these results could lead to potential treatments for conditions such as depression or neurodegenerative diseases.”