It is common to assume that differentiation - the process by which buyers match their unique specialization - is a "one-way street". A new study by Prof. Dov Tzipori from the Weizmann Institute of Science raises the possibility that in quite a few cases the cells may "move backwards" in the differentiation pathway, and return to earlier stages.
Embryonic stem cells differentiate into all types of cells in the body. In contrast, the relatively limited stem cells of the adult grow a variety of specialized adult cells belonging to a particular tissue. However, for all the stem cells, there is a uniform dogma: it is common to assume that differentiation - the process by which acquirers adapted their unique specialization - is a "one-way street". A new study by Prof. Dov Tzipori from the Weizmann Institute of Science raises the possibility that in quite a few cases the cells may "move backwards" in the differentiation pathway, and return to earlier stages.
In his laboratory in the Department of Molecular Biology of the Cell, Prof. Birds researches mesenchymal stem cells. Unlike other types of stem cells, which are located in designated sites, the mesenchymal cells are scattered throughout the body. They are characterized by the ability to differentiate into three types of tissue: bone, cartilage and fat - a sort of "golden triangle". According to the accepted, one-way scenario, a mesenchymal stem cell may divide symmetrically, creating two identical stem cells, or asymmetrically, in which one cell is formed that retains the properties of a stem cell, and another cell that begins the differentiation process. Then, during several division cycles, the next generations of cells continue to differentiate gradually, until mature specialized cells are formed. During the intermediate stages, the cells gradually lose their specialization potential: in each cycle of division, the variety of tissues and the type of cells they can create decreases.
This model - which also includes the idea of the "golden triangle" - was mainly accepted thanks to a scientific article published in 1999. The mesenchymal stem cells were placed at the top of the triangle, as they are capable of producing all three tissues. Most of the follow-up studies done in these cells, and in other stem cells, were based on it. However, even then, Prof. Tzipori wondered whether these findings really accurately reflect what is happening in the body. First, experiments with fruit flies revealed evidence that certain mature cells in the reproductive system can "regress" to the state of a stem cell. Second, his studies in mesenchymal cells showed that these cells show a less orderly behavior than that described in the one-way model. Already in the mid-80s of the 20th century, Prof. Tzipori noticed that when the environmental conditions of the cells change slightly, some of the sorted cells lose their mature properties, and return to a state that appears to be unsorted.
In 2004, in an article published in the scientific journal Nature Reviews Genetics, Prof. Tsifuri proposed a thought approach based on the idea of "race state", or "racism", that is, a state of high differentiation potential into which almost any cell can enter at any point in time, under certain conditions , and this is compared to the idea of having a "stem cell", which is an absolute category. If so, the characteristic of "raciality" is a fluid state that the cell may enter and leave. In addition, Prof. Tzipori raised the possibility that such activity may occur spontaneously in the body. In fact, he pointed out, the appearance of new stem cells in the adult body may be due to the fact that adult cells have reacquired the "race" feature, and not just stem cell division.
The "golden triangle" model (above) versus the proposed "racial situation" model. According to the golden triangle model, the mesenchymal stem cell divides asymmetrically, and after several cycles of division three types of cells are formed: bone, cartilage and fat. According to the "race state" model, according to which the cell can move forward - but also backward - between different differentiation states
Just two years later, the idea of "race" was strengthened, when Japanese scientists succeeded in giving this property to mature cells, which were returned to the most primitive cellular state - similar to embryonic stem cells. This process is done by artificially infusing the expression of a certain genetic program in the cells. However, most scientists did not believe that this process could occur in the body spontaneously.
In the current study, which was recently published in the scientific journal Stem Cell, Prof. Tzipori and the members of his group sought to test the degree of rigidity of the differentiation pathway of mesenchymal cells: does the accepted description, which includes an inflexible chain of events, indeed correctly reflect what is happening in reality? The team of scientists isolated mesenchymal cells from a mouse, grew them in vitro, and analyzed the process of differentiation and division using modern single-cell tracking methods. The research was started five years ago by the (then) research student Dr. Ofer Shoshani, and later he was joined by other members of the group, including Dr. Orli Ravid, Hassan Masalha, Ella Aharonov, Yossi Ovadia, and Dr. Mirav Pevzner-Fisher, and Dr. Dina Leshkowitz from the bioinformatics unit of the institute.
The scientists were able to capture mesenchymal cells in the intermediate stages of differentiation. According to the conventional model, each generation of cells was expected to show a gradual decrease in differentiation potential. However, the findings were different: some of the cells did lose some degree of potential - for example, the ability to differentiate into one of the three tissues, but their siblings, or their cousins, reacquired this ability at different time points. The resulting picture was not of a straight, one-way street, but of a more complex pathway, where cells can move from one state to another and back again. Although the scientists tested the potential of differentiating into one of the three "golden triangle" tissues - fat, bone or cartilage - they noticed signs that the mesenchymal cells acquire the ability to differentiate into other tissues, such as endothelial or epithelial-like cells.
According to Prof. Tzipori, it is possible that these cells have reacquired high degrees of differentiation potential that they lost in the past, and this is because they were under stress - in this case, they were removed from their natural environment in the mouse's body and transferred to a test tube. This assumption is consistent with another observation of the scientists: the cells tended to return to the "race" state less often when grown in an oxygen-poor environment. Low oxygen levels characterize the situation prevailing in the immediate environment of the body's stem cells normally, while high levels of oxygen are associated with stressful situations, such as injury. In light of the findings, Prof. Tzipori believes that the mesenchymal cells "jump" into a state of higher differentiation potential in situations such as tissue damage, when many types of new cells are quickly required.
Prof. Tzipori: "Our findings show that mesenchymal cells with a low differentiation potential are actually intermediate cells, which, due to being removed from their natural environment, were exposed to a state of stress, and therefore jumped back to the 'race state'. For this reason, the use of the accepted method for defining 'race', based on stem cell cloning, may be misleading. A lot of research has been based on the one-way model in the last 15 years, but our findings show that we have to rethink even the most basic assumptions regarding the ways to renew the stock of stem cells in our body."
