Neural stem cells divide to generate neurons throughout life. But as the stem cells age, the neurogenic potential diminishes. Research led by Prof. Sebastian Jessberger has shown that a lateral diffusion barrier in the endoplasmic reticulum protects juvenile stem cells by asymmetric segregation of damaged cell components. This barrier is less effective in aging stem cells, resulting in slower cell division. The research was published in the September 18 issue of Science.
Neural stem cells (NSCs) generate new neurons throughout life in two distinct areas of the mammalian brain, the subventricular zone lining the lateral ventricles and the hippocampal dentate gyrus. Failure in the generation of new neurons in the adult brain has been associated with neuropsychiatric disease, such as cognitive aging and depression. As stem cells age, their division slows down and their neurogenic potential declines. But what causes the aging of stem cells?
Asymmetric cell division helps rejuvenate stem cells
During cell division, yeast establishes a lateral diffusion barrier in the membrane of the endoplasmic reticulum (ER) that plays an important part in the asymmetric segregation of aging factors between the mother and the daughter cell. Dr. Darcie Moore, postdoc in the group of Jessberger at the Brain Research Institute of the UZH, wanted to know whether such a diffusion barrier also exists in mammalian cells. To this end, she and her colleagues used neural stem cells expressing green fluorescent protein (GFP) reporters targeted to the ER membrane. They then repetitively photobleached a small region of the cell and showed that the bleached ER membrane proteins were not evenly distributed between mother and daughter cells. This result demonstrated that in mammalian cells a lateral diffusion barrier in the ER exists and that the diffusion barrier promoted asymmetric segregation of cellular components between mother and daughter cells.
Diffusion barrier weakens with age
The researchers next asked which cellular components the barrier might segregate. To this end they analyzed the distribution of ubiquitinated proteins (that are indicative of protein damage) in dividing cells and found that damaged proteins are retained in the daughter cell, whereas the stem cell stays relatively free of damage. Importantly, Moore and colleagues found that the strength of the lateral diffusion barrier weakens with advancing age of stem cells, leading to reduced asymmetry of damaged protein segregation. This could be one of the mechanisms responsible for a reduced regeneration capacity in the aged brain as stem cells that retain larger amounts of damaged proteins require longer for the next cell division.
Sebastian Jessberger says: “This is an exciting new mechanism involved in stem cell division and aging. But as of now we are only just beginning to understand the molecular constituents and the true meaning of the barrier for stem cell division in the brain.” The question that remains to be answered is whether this is a general mechanism that also occurs in other somatic stem cells or any other immortal cells, such as cancer cells.
A mechanism for the segregation of age in mammalian neural stem cells. Moore DL, Pilz GA, Araúzo-Bravo MJ, Barral Y, Jessberger S. Science. 2015 Sep 18;349(6254):1334-8. PubMed Abstract
Image: The stem cells asymmetrically segregate damaged proteins (red) between the mother and the daughter cells (on the left: DNA grey). Responsible for this is a diffusion barrier. The strength of the barrier weakens with advancing age. This leads to reduced asymmetry of damaged protein segregation (on the right). (Image: UZH)