Senescent cells, the key trainers in the embryo

Gene Regulation, Stem Cells and Cancer

CRG researchers have found senescent cells in embryos for the first time, presenting evidence that senescence is crucial to proper development

For most culés –fans of Barcelona football team- Josep Guardiola was the greatest trainer in the club’s history. His own unique way of seeing football, understanding how to play and his contagious passion for the game, led Barça to sporting excellence. During his 4 years leading the team, Barça won two Champion’s Leagues, three Ligas, two Club World Cups, two European Supercups, two Copa del Rey competitions and three Spanish Supercups. Not bad!

But then Guardiola, unfortunately for most of his fans, decided to leave Barcelona. In a press conference, he explained that these four years had been very demanding and that he was “leaving with the sensation of having done a good job”. He explained “I am proud of what I’ve done here. I am leaving at peace with myself”. And then, he quit.

A similar thing happens inside your body at certain moments in your life. Yes, you do have some kind of tiny Guardiolas organising the play of your tissues and cells; these special trainers tell the organism’s players what to do; they instruct them, give them a mission, and when the work is done, they simply retire. Unlike Guardiola, they do not happily move to another tissue to continue training; they are killed. It is more like the awful fate of the male praying mantis after copulation. Once he has done what he has to do, game over!

This is what a group of researchers at the Centre for Genomic Regulation (CRG) have discovered and published in the journal Cell. They have found that there are senescent cells in some regions of the embryo that are crucial for correct growth and patterning. “These cells secrete a lot of different factors and we believe they are telling the neighbouring tissues how to grow, to proliferate, and which way to form”, explains Bill Keyes, a biologist leading the Mechanism of Cancer and Ageing Laboratory at the CRG.


Three types of senescence

Traditionally, senescence has been associated with the end stage of a cell. In 1961, a pair of biologists, Leonard Hayflick and Paul Moorehead, found that, contrary to what was thought at that time, cells would divide 50 times and then stop and become senescent. “It was found that each time they divide, telomeres shorten. Maybe it is a kind of quality control establishing cell life as a defined period of time”, Keyes considers. This kind of senescence has long been linked to the ravages of age, such as wrinkles, cataracts and arthritic joints.

But then a similar process was discovered related to oncogenes. As cells divide aberrantly in response to oncogenic stimulation, they accumulate damage in their DNA. When they are too damaged, a set of genes is switched on causing the cell to stop growing. Surprisingly, these cells then secrete a cocktail of chemicals, which can cause chronic inflammation and, as this is a risk factor, the immune system detects the senescent cells and kills them, as a protective process.

“Now we are seeing a similar mechanism during development, not related to telomere shortening or DNA damage. We have found senescence in the embryo, at the beginning of life. And what is more important we have discovered it is not just an end stage, but a process that can instruct patterning and tell other cells how to behave”, points out Keyes.

The three types of senescence share many features, in that they are all arrested in proliferation and are removed by immune cells as a way of finally disposing of them. In addition, they all seem to be sending signals to the local environment, giving the neighbouring cells instructions. In the first two types of senescence (telomere shortening and oncogene-induced), these instructions may lead to premature ageing and cancer.

But in the case of the embryo, the CRG researchers describe senescence as a fundamental part of the biology of two major signalling centres that helps control normal limb and nervous system development. By sheer coincidence, Manuel Serrano’s group, from the National Cancer Research Centre (CNIO), identified identical processes in other regions of the embryo, including the kidneys and the ear.

“Senescence may occur not only to instruct but also remodel tissues”, highlights Keyes. In the limbs, the CRG group thinks that senescent cells secrete growth factors, telling the underlying tissue both to proliferate and what kind of cell to become: bone, blood, skin, etc. When the limb is formed, these instructing cells are no longer needed, so they are removed. They go into apoptosis and are then cleared by macrophages. Any disruptions to this process of senescence-instruction may contribute to birth-defects, like Spina bifida, exencephaly or limb defects.

In this sense, in embryonic cells, senescence is just a state. “We do not know whether this happens in the whole body, but we suspect there will be more senescence in the embryo”, says Keyes.


A weapon against cancer?

From a cancer point of view, the work by Keyes and his colleagues sheds light on the role of senescence in the early stages of the illness. For a long time, it was believed that it was a mechanism designed to protect us from tumour formation. But what these CRG researchers suggest is that senescent cells could be telling the neighbouring cells to proliferate, actually making the cancer worse.

“This had also been seen in previous studies, but the reason is not fully understood and questions remain about its paradoxical role, because if a single cell has an oncogenetic mutation, that cell will be protected from becoming cancerous, as it will undergo senescence. The side effect is it can tell other cells how to behave, change their fate or proliferate more”, explains Keyes. So this mechanism really is a doubled-edged sword.

Reference work:

Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, Yosef R, Pilpel N, Krizhanovsky V, Sharpe J, Keyes WM.
“Senescence is a developmental mechanism that contributes to embryonic growth and patterning.”
Cell, 155(5):1119-30 (2013).