Like a cog in a Swiss watch

Gene Regulation, Stem Cells and Cancer

A team of researchers from the CRG discover how, minute-by-minute, the circadian rhythm modulates skin stem cell function

Have you ever wondered where all the dust that accumulates on your desk comes from? You might think about your pets, or maybe the particles that come in from the street every time you open the window, but the fact is that 70% of it is human skin. Epithelial cells that flake off and turn into that dust. And, although we are not aware of it, our skin regenerates almost every day.

It is, without doubt, a fascinating organ. If we could take it off, we would see that it takes up little more space than a bath towel, between 1.5 and 2 m2 in area and weighing around 3 kg. Its function is essential to our survival, because, on the one hand, it provides a barrier against the environment, protecting us from attacks and making us waterproof (if not, imagine the disaster whenever we put our hand in a basin of water; we would get soaked, literally, to the core!).

And on the other, our skin, which separates us from the environment, also connects us with it and gives us a huge amount of information, as though it were a kind of tactile brain.

It can perform all of these functions thanks to a sort of internal clock, rigorous and precise, the circadian rhythm, which regulates the behaviour of stem cells in tissues, as was discovered in 2011 by a team of researchers from the Centre for Genomic Regulation (CRG) in Barcelona, headed by ICREA research professor Salvador Aznar-Benitah. “We saw that the cells were able to distinguish the day from the night and that this was crucial for their functionality.”

However, this CRG team did not stop there. Aznar-Benitah had a gut feeling and the technological advances of the past two years played in his favour. “And what if the same happens in stem cells as happens in human beings, that we behave differently and have different needs at each moment of the day?” he wondered.


Minute-by-minute

As with other many tissues, until a few years ago it was thought that a single stem cell was responsible for maintaining the different populations of cells in a tissue. However, it was proved that it was not like this, but rather every part of the skin – epidermis, sebaceous glands and hair follicles- had its own reserve of stem cells.

Aznar-Benitah suspected that all those stem cells, surely, must behave differently, judging by the function of each part of the skin. “The epidermis is renewed almost on a daily basis, but the same does not happen with hair on the arm; it does not drag on the ground because it doesn’t stop growing”, jokes this researcher. “Hair follicles go through long periods of quiescence”.

A much more detailed molecular study allowed them to look at what the cells were doing minute-by-minute. “Before, we had placed the division very generally between day and night, but we have now seen that there are more divisions, that cells can tell if it is 11 am or 7 pm. And that that is essential for their functionality, to protect themselves from what can do them most harm, ultraviolet light from the sun, and to decide at which point they should divide and differentiate”, says Aznar-Benitah, describing the results of the study published in an article in the journal Cell Stem Cell.

Apparently, stem cells have genes that control the biological clock, establishing activity and time intervals throughout the 24 hours of the day. This enables them to better adapt their functions to each moment of time and the environmental characteristics. So, during the hours of greatest solar radiation, they protect themselves and establish a protective barrier against bacteria and viruses (whose activity, interestingly, is also marked by the circadian rhythm). In contrast, during the evening and night they are responsible for repairing any damage that has taken place during the day, dividing and replenishing the lost cells.

Their acting in this way does not depend on whether or not they are directly exposed to the light, it is an endogenous mechanism. Even in Scandinavian countries, where there are six months of day and six of night, the circadian rhythm works the same way. It is a mechanism that has been forged over hundreds of millions of years of evolution to ensure better adaptation and therefore the survival of the organisms that inhabit the Earth. Since our planet stabilised and established its 24-hour rotation, life has been adapting to that cycle and even deep-sea fish, which never see the light, are governed by this internal clock.


Cancer, ageing and circadian rhythms

When this internal clock goes out of sync, problems start. In studies on animal models, like mice, it has been seen that when the cycles of light are altered, the skin stem cells of the rodents lose the ability to know what time it is. And this makes the tissue age much earlier, as it does not know when it has to be protected from ultraviolet light, and it accumulates many mutations. In the long run, it may even predispose the tissue to tumour development.

In fact, it is known that pilots, air stewardesses and shift workers who continually change their schedule of activity have an increased susceptibility to developing metabolic problems, obesity, diabetes, and even cancer. And this has to do with the tissue’s inability to know if it is day or night and what it should be doing at each moment.

“We have managed to find out how the circadian rhythm of stem cells works, but it is all so much more complex. Because this internal clock has to operate synchronously with that of the neighbouring cells, which secrete growth factors that tell the stem cell what to do at any given moment”, adds Aznar-Benitah, who joined the Institute of Biomedical Research (IRB) in Barcelona as a researcher in September 2013.

Basically, it is like Swiss watch, made up of different cogs. Its precise timekeeping depends on the correct performance of each one of those wheels and the synchronisation between all of them.

Reference work:

Janich P, Toufighi K, Solanas G, Luis NM, Minkwitz S, Serrano L, Lehner B, Benitah SA.
“Human epidermal stem cell function is regulated by circadian oscillations.”
Cell Stem Cell, 13(6):745-53 (2013).