Scientists claim that the age-related decline in numbers of neurons in the hippocampus may be due to a gradual exiting of its stem cell population. A Cold Spring Harbor Laboratory (CSHL)-led team has found that stem cells in the hippocampus can actually only go through one cycle of dividing into neural cell progenitors before they lose their stemness and themselves differentiate into mature astrocytes.
The disposable nature of neural stem cells effectively leads to an ever-shrinking stem cell pool and hence a reduction in brain cell renewal as we age, claim Grigori Enikolopov, Ph.D., and colleagues. They report their research in Cell Stem Cell in a paper titled “Division-Coupled Astrocytic Differentiation and Age-Related Depletion of Neural Stem Cells in the Adult Hippocampus.”
Stem cells in many tissues have been shown to go through cycles of self-renewal followed by periods of quiescence, Dr. Enikolopov and colleagues report. The conventional model is that a stem cell will periodically come out of its quiescent state, undergo asymmetric division to generate tissue progenitor cells and renew itself, and then return to quiescence until the next round of division is triggered. This cycle is believed to help maintain the size of the pool of stem cells while limiting replication to reduce the probability of accumulating mutations.
This tenet has also held true for brain stem cells, and scientists have postulated that declining numbers of neurons in the aging brain could relate either to an increase in neural stem cell quiescence, a decrease in stem cell productive division or survival of their progeny, a reduction in neuronal fate commitment, or the loss of neural stem cells through death.
Using mouse models in which brain stem cells and progenitor cells are differentially tagged, the CSHL team has now shown that hippocampal stem cells don’t behave in the same way as the perpetually self-renewing stem cells in other tissues. Instead, stem cells in the brain that are triggered to come out of quiescence go through a rapid series of cell divisions to generate their progenitor cells and then themselves convert into mature hippocampal astrocytes and so leave the stem cell pool.
“These results support a model in which a stem cell of the adult brain can be described as a ‘single use’ or a ‘disposable’ unit,” the authors write. The brain stem cell is effectively “quiescent for the entirety of its adult lifetime, activated to undergo a series of rapid asymmetric divisions (with progeny, after additional divisions and massive elimination, maturing into neurons), and then, via differentiation into an astrocyte, abandoned in its capacity to act as a bona fide stem cell.”
This model would fit in with the age-related decrease in production of new neurons, the observed increase in astrocytes, and disappearance of hippocampal neural stem cells, they suggest. The CSHL researchers are now investigating whether it may be possible to trigger this population of astrocytes to revert back into their original stem cell state and rejoin the stem cell pool.
The published findings also beg the question of what effect exercise and drugs (such as Prozac) that are known to promote neuronal generation have on the brain’s apparently finite stem cell pool, Dr. Enikolopov remarks. “Having the ability to produce new neurons is obviously good, but since adult brain stem cells seem to follow a ‘use it and lose it’ rule, does activating neuronal production too much exhaust the stem cell pool prematurely?”
The hope is that while diseases and injury that activate stem cells directly may result in a depletion of the stem cell pool, other triggers such as exercise or drug treatment work to stimulate the downstream progeny of stem cells to differentiate into mature neurons rather than use up the stem cell pool itself. Another avenue of research by the CSHL team is therefore to identify drugs that can stimulate neuronal differentiation from progenitor cells without having to tap into the stem cell population.