Towards Restoration of Neural Stem Cell Function in the Old

Every tissue in the body supported by its own specialized small stem cell populations. The vast majority of cells in the body, known as somatic cells, are limited in the number of times they can divide. Their telomeres shorten with each cell division, and they become senescent or self-destruct when reaching the Hayflick limit on replication, triggered by short telomeres. Stem cells have no such limitation, and use telomerase to maintain telomere length regardless of the number of divisions they undergo. They divide asymmetrically to generate daughter somatic cells with long telomeres that can replace lost somatic cells in order to maintain tissue function. This split between a small privileged cell population and a large, limited cell population most likely evolved because it greatly reduces the risk of cancer.

Unfortunately, stem cell activity declines with age, producing a slow decline of tissue function, ultimately causing disease and death. This may also be an adaptation that exists to reduce cancer risk. From a mechanistic point of view, it appears to be a reaction to rising levels of molecular damage, and the consequences of that damage, such as chronic inflammation and other forms of altered signaling between cells. While some stem cell populations are damaged and diminished in and of themselves in older individuals, such as hematopoietic stem cells, others, such as muscle stem cells, have been shown to be just as capable in old age as in youth, but much less active. The stem cells lapse into extended quiescence and cease to create daughter somatic cells.

Neural stem cells appear more akin to muscle stem cells than hematopoietic stem cells in the matter of whether or not they still exist in old individuals and are capable of activity, given the right instructions. The activity of neural stem cells is an important portion of neuroplasticity, the ability of the brain to generate new neurons that integrate into existing neural circuits or form new neural circuits. This is the basis of cognitive function and also of repair in the brain. To the degree that the supply of new neurons declines, this is a slow road to neurodegeneration. Many other issues need to be fixed in the aging brain, such as chronic inflammation, slowed drainage of cerebrospinal fluid, and the aggregation of proteins associated with neurodegenerative conditions. Nonetheless, stem cell function must be restored in some way.

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As we age, our brains' stem cells 'fall asleep' and become harder to wake up when repairs are needed. Despite efforts to harness these cells to treat neurological damage, scientists have until recently been unsuccessful in decoding the underlying 'sleep' mechanism. Now, researchers studying brain chemistry in mice have revealed the ebb and flow of gene expression that may wake neural stem cells from their slumber.

The team focused their attention on protein Hes1, which is strongly expressed in the adult cells. This normally suppresses the production of other proteins such as Ascl1, small amounts of which are periodically produced by active stem cells. Monitoring the production of the two proteins over time, the team pinpointed a wave-like pattern that leads to stem cells waking up and turning into neurons in the brain. When they knocked out the genetic code needed to make Hes1, the cells started to make more Ascl1, which then activated almost all the neural stem cells.

"It is key that the same genes are responsible for both the active and quiescent states of these stem cells. Only the expression dynamics differ between the two. A better understanding of the regulatory mechanisms of these different expression dynamics could allow us to switch the dormant cells on as part of a treatment for a range of neurological disorders."

High Hes1 expression and resultant Ascl1 suppression regulate quiescent vs. active neural stem cells in the adult mouse brain

Somatic stem/progenitor cells are active in embryonic tissues but quiescent in many adult tissues. The detailed mechanisms that regulate active versus quiescent stem cell states are largely unknown. In active neural stem cells, Hes1 expression oscillates and drives cyclic expression of the proneural gene Ascl1, which activates cell proliferation. Here, we found that in quiescent neural stem cells in the adult mouse brain, Hes1 levels are oscillatory, although the peaks and troughs are higher than those in active neural stem cells, causing Ascl1 expression to be continuously suppressed.

Inactivation of Hes1 and its related genes up-regulates Ascl1 expression and increases neurogenesis. This causes rapid depletion of neural stem cells and premature termination of neurogenesis. Conversely, sustained Hes1 expression represses Ascl1, inhibits neurogenesis, and maintains quiescent neural stem cells. In contrast, induction of Ascl1 oscillations activates neural stem cells and increases neurogenesis in the adult mouse brain. Thus, Ascl1 oscillations, which normally depend on Hes1 oscillations, regulate the active state, while high Hes1 expression and resultant Ascl1 suppression promote quiescence in neural stem cells.

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