University of Ottawa Researchers Have Found A New “Fate” For Aging Stem Cells

Death is a normal part of the life cycle for cells. They form, grow, perform their expected duties and then, after a while, face a predictable fate. When the time comes, the cell undergoes a programmed process, known as apoptosis  to break down many of the internal components and pave the way for the final end.

One of the first steps in apoptosis involves the mitochondrion  This cellular organelle is mainly responsible for energy production in the cell . But when the time comes to call it quits, the structure begins to break down into fragments. As this happens, the nucleus is prompted to make proteins responsible for deconstructing other cellular structures. In addition to the proteins, another group of molecules, known as reactive oxygen species, or ROS, are also formed. These molecules seek out proteins and damage them with incredible efficiency.

Fragmentation of the mitochondria is a telltale sign of a cell’s fate. Yet it turns out the result may not always be death. For a particular group of cells known as neural stem cells, there may be another option:  lead a new type of life.

The revelation comes as a result of a recent study from a University of Ottawa research team led by Ruth Slack and her postdoctoral fellow, Mireille Khacho. They recently published in the journal Cell Stem Cell a fascinating observation of life in the face of the signals of death. Based on their work, there may be a new understanding of how stem cells live and more importantly, how they instead of die, differentiate.

Stem cells are the foundation of life acting as the first generation for all cell types in the body. They multiply over the course of life, a process known as proliferation. But, when they are called upon, they change their identity, transforming – or differentiating – into different types of cell such as bone, skin, muscle, immunological cells, and, in the case of neural stem cells, nerves. This transformation allows for self-renewal so we never lose out on the cells we need to stay alive.

Normally, the population of proliferating stem cells is maintained however, as we grow older, the numbers drop As this happens, the ability of the body to renew itself decreases and the impact of damage on already living cells tend to add up. Because of the involvement of the mitochondria and ROS in cell death, they have been regarded as one of the main suspects in this stem cell reduction. .

Research into the contribution of mitochondria and ROS to stem cell aging has been examined for well over a decade and several contributing mechanisms have been identified. Yet no one understood exactly how this depletion occurs. For Slack’s group, understanding this mechanism became the heart of the study.

The group conducted the experiments using mice. At first, the team chose to examine the effects of mitochondrial fragmentation and ROS formation in embryos during brain development. The team could then observe how these cells reacted to the well-known signals of death.

As anticipated, proliferating stem cells had an elongated mitochondrial structure meaning they were alive and well. But, stem cells with fragmented mitochondria were not dying as one might expect. Instead, they were differentiating. To be sure this observation was real the team used genetically altered mice only capable of forming fragmented forms of the organelle. Just like the normal mice, the stem cells acted in the same way by differentiating.

As to what may have contributed to this strange result, the team found the ROS played a major role. Unlike normal apoptosis, the ROS levels rose only moderately, but this was sufficient to signal a change of cell fate back to the nucleus. In this context, instead of producing death-associated proteins, the genes produced factors associated with differentiation. For some reason, the programming in neural stem cells was different at the genetic level.

To get a better idea of what happened, the group examined the cell’s genes to determine which ones were being produced leading to this shift in stem cell fate. They found the expression of one particular gene, nuclear factor (erythroid-derived 2), of Nrf2 for short, was increased. The gene is known as an oxidative stress response gene and is normally expressed to help combat elevated levels of ROS As the levels of Nrf2 rose, so did the chance for differentiation and stem cell depletion.

While significant insight into the mechanism has been found, it was still limited to the embryo. To appreciate the effect on adults, the team had to work with fully grown animals. They did this by letting mice to grow to six weeks of age and then sparked the same type of mitochondrial fragmentation in neural stem cells. Within a few weeks, the mice began to display learning impairment. In essence, the loss of adult stem cells was causing consequences at the behavioural level.

The results of this study have several implications in human health. Although the experiments were conducted in mice, they outline a rather interesting perspective on aging and the brain. As increased fragmentation occurs, the stem cells will continue to differentiate and deplete the population. As a result, there is less opportunity to self-renew when damage occurs. In the context of brain health, this could lead to a higher risk for neurodegenerative disorders.

The study also opens the door to possible therapeutic options as an exploration of potential antioxidants to reduce the levels of ROS during mitochondria fragmentation. There is already clinical evidence to suggest antioxidants such as Vitamin E may help reduce the risk for Alzheimer’s disease and other neurodegenerative disorders.   In light of this study, there is even more reason to learn whether we can use these chemicals to preserve the stem cell population throughout our lifespan and stave off disease.

Text by Jason Tetro, for CAN-ACN