Neural stem cells segregate aging factors during cell division by establishing a diffusion barrier [with video]

The ability of somatic stem cells to regenerate tissue is reduced with aging, resulting in effects such as cognitive impairment, reduced immune response, deterioration of skeletal muscle, and difficulty in wound healing. Using neural stem cells of the brain, the authors suggest the mechanism behind this age-dependent stem cell dysfunction is the cell's inability to segregate accumulated damage to its progeny during cell division due to a weakened diffusion barrier.

HFSP Long-Term Fellow Darcie Moore and colleagues
authored on Fri, 16 October 2015

Neural stem cells generate new neurons throughout life in the mammalian brain. This process, called adult neurogenesis, is critical for certain forms of learning and memory and has been implicated in a number of neuro-psychiatric diseases, among others major depression and cognitive aging. But how do adult neural stem cells manage to generate new neurons throughout life without losing their capacity for cell proliferation? We have identified a novel mechanism by which neural stem cells stay relatively free of cellular aging factors (such as damaged proteins that accumulate with age) by establishing a diffusion barrier during cell division that is associated with the asymmetric segregation of aging factors between stem cells and their progeny. These findings shed new light on the mechanisms underlying asymmetric stem cell division and may open new routes to target age-dependent alterations of stem cell activity in human disease.

Figure: In this dividing neural stem cell, ubiquitinated proteins (red) are asymmetrically segregated to one of the daughter cells (nuclei are labeled in blue).

Yeast is good for making wine, bread, and brewing alcohol, but who knew it would also be a good model for neural stem cells in the mammalian brain? In yeast, with every division, cellular aging factors are asymmetrically distributed between the mother and the daughter cell, allowing for rejuvenation and full life span of the daughter independent of the age of the mother cell. At least partially responsible for this is the presence of a diffusion barrier that restricts movement of molecules from one side to the other side of the cell during cell division. We have investigated if similar mechanisms exist in mammalian stem cells that are required to divide many times, and ultimately begin to dysregulate with age, becoming more quiescent and unable to do their job. Could stem cells have a diffusion barrier that segregates damage to their daughters each time they divide? 

We found that neural stem cells isolated from the adult brain establish a diffusion barrier in the membrane of the endoplasmic reticulum, and that this barrier weakens with age when the activity of neural stem cells dramatically declines. Supporting a role for the barrier in the sorting of cellular aging factors, we found that the strength of the barrier was associated with the asymmetric segregation of damaged proteins to only one daughter cell after cell division and that the non-stem daughter cell retained the damaged proteins, whereas the stem cell remained cleaner. This effect was less prominent with advanced age when the barrier weakens. Interestingly, the cost of receiving more damage was that the daughter cell that inherited more of the damaged proteins took longer to divide. Thus, the inability of the stem cell to remain “clean” may contribute to the reduction in function of stem cells in the aging brain. 

One key question to be answered is whether the barrier is established in all somatic stem cells of the body (or even in all dividing cells in general). The answer to this question may open new routes to target age-dependent alterations of stem cell activity in human disease.

Video: Vimentin inheritance in apical progenitor in embryonic brain

Reference

A mechanism for the segregation of age in mammalian neural stem cells. Moore, D. L., Pilz, G. A., Arauzo-Bravo, M. J., Barral, Y. & Jessberger, S. Science 349, 1334-1338, doi:10.1126/science.aac9868 (2015).

Pubmed link