The secret ability of stem cells
An article published in Science quotes the work of an MIT team which tries to unveil the secret ability of stem cells to replicate indefinitely and restrain the potential to turn into any kind of cells. Dr. Vincenzo Pirrotta, a molecular biologist at the Rutgers University of Piscataway in New Jersey, answer Science at Stake questions.
Can you firstly explain what exactly a stem cell is?
A stem cell is a kind of cell that is able to propagate itself, maintain itself without differentiating. There are different kinds of stem cells with different level of potentiality, embryonic stem cells are among the most pluripotent stem cells that we know, they can give rise to any kind of differentiated cells. But there also neuronal stem cells, muscle stem cells so there are many kind of different stem cells that can differentiate to give rise to at least a subset of specialized differentiated cells.
For what purpose are stem cells used?
Today stem cells are primarily used for research they are not yet at present utilised for practical purposes or therapeutic purposes although I suppose that such applications may be in the works but they would not be available soon. The question about how to use stem cells in a practical way for therapeutic purposes is a complicated one and it's going to take still a number of years before it would be possible to take stem cells and make them differentiate into any kind of specific tissue that we desire.
In the Science article you say that the papers from Rudolf Jaenisch and Richard Young but also from Bradley Bernstein about polycomb protein “provide a wealth of detailed information on what keeps ES cells pluripotent”. Can you develop?Yes of course, a cell that is potentially able to differentiate into any kind of differentiated cell must at the same time be able to prevent itself from differentiating spontaneously: to remain pluripotent it has to keep repressed all of the genes that would initiate one or another differentiation pathway. These genes have to be kept under control, they have to be kept repressed and this is shown by the results of the teams of Richard Young, Rudolph Jaenisch and Eric Lander, who have published papers on the subject recently. The major job of keeping these differentiation genes under control is the job of the polycomb group of proteins, these are proteins that form repressive complexes that are specifically targeted to keep differentiation genes repressed. That is they are not available for expression, they are not functional. So it is very reasonable that stem cells should keep differentiation genes repressed. What stem cells have to be able to do is to keep these genes repressed but on the other hand also keep them available, they need to be able to be turned on whenever the stem cells want to differentiate or are stimulated to differentiate to one or another different pathway. This is really the exciting question, how are these differentiation genes repressed and yet not completely repressed, not completely locked up, they are still available, they are in a state in which they are easily switchable back to the active state whenever a suitable signal arrives and this is one of the results or one of the suggestion that came out of one of this articles that perhaps the polycomb repression of the differentiation genes in stem cells is delicately poised between the silent and the active state, between the repressed state and the functional state. Exactly how this works we do not exactly know but what this paper demonstrates is that the repressed genes have the marks of repression but they also have some of the marks of genes about to be activated or switched on to an active state. So the question today is what exactly is the difference between genes that are repressed but poised and genes that are permanently repressed and what are the signals that make them switch back to the active state.
the implications of this discovery?
The implications are that now we are beginning to know more about the mechanisms that control genomic programming that is the program of gene expression that control what a cell is going to able to do, how it is going to be able to differentiate, what kind of differentiated tissue it is going to be able to produce. We know now some of the mechanisms that are involved, we need to be able to control and manipulate these mechanisms. At least we know what the target gene are and we know perhaps what these Polycomb proteins do at the target gene. Now we need to know how to manipulate them.
the next steps that need to be made in the stem cells research field?
I think the important next step is to find out what are the signals that are required to regulate the activity of these repressed genes and to control the repressive mechanism that keeps them under control? How can they be switched back on? Is it possible to determine which differentiation pathways are going to be switched back on? Ideally one would like to be able to trigger a pluripotent stem cell population to differentiate at will into heart cell, skin cell, nerve cell, muscle cell and we don't know how to do that quite yet.
How long do you think it could take?
I think to do simple things like simply take stem cells and differentiate them into muscle might not take really long and might be a matter of a few years , two three years. To make those muscle cells assume some specific figuration, that is make a differentiated mussel cell usable for, for example, regenerating muscle tissue, that make take a little bit longer. The hope I think in the long run would be to be able to take cells from the patient, differentiated cells perhaps or at least partly differentiated cells, dedifferentiate them so that they become pluripotent cells and then re-channel them into a specific differentiated partway to produce whatever tissue the patient is in need of. This is I think will take considerably more time, it's hard to say how much because the researches are so unpredictable, sometimes things move extremely fast sometimes many problems become visible after you start doing some research. But I think is something for the next five ten years.
Thank you, Dr. Vincenzo Pirrotta, for answering Science at Stake questions
Interview by Francesca Gilibert