Induced pluripotent stem cells

The usual career of a living cell proceeds from its beginning as a stem cell in the embryo through a process of differentiation where it becomes more and more specialized until (in most cases) it finally takes its place in some tissue as a terminally differentiated cell. This process involves various genes being switched on or off. Usually in the past this process has been thought of as being more or less irreversible. This leads to the great interest in embryonic stem cells as a potential basis of the treatment of various illnesses by regeneration of certain types of cells. Unfortunately embryonic stem (ES) cells have two big problems associated with them. The first is that their use raises ethical concerns in many people which act as a powerful inhibitor of the development of the technology. The other is that they may involve medical dangers. If the cells develop in the wrong direction they may lead to tumours, especially the type called a teratoma where cells are found which are of the wrong type of tissue (and often of many types) for the place they are in.

It was discovered in 2006 by Shinya Yamanaka and his associates that the usual development can be run backwards, producing stem cells from terminally differentiated cells, for instance skin cells. They named these cells induced pluripotent stem cells (iPS cells). On the web page of the National Institutes of Health where they have videos of lectures (http://videocast.nih.gov/) there is a talk given by Yamanaka on January 14th, 2010 which is inspiring and at the same time presented in an entertaining style. The introduction by Francis Collins, director of the NIH suggests that Yamanaka will not have to wait long for his Nobel Prize. iPS cells are an ethically safe alternative to ES cells. Their medical safety does not look so good at the moment. Under some circumstances the safety profile of iPS cells is similar to that of EC cells. Under other circumstances a subset of the cells seem to be refractory to differentiation and can then produce teratomas at a later time. It is necessary to learn to control their development better before they can be used in regenerative medicine. Of course it would be important to know what characterizes this subset. Yamanaka suggests that this may have to do with epigenetic factors and this ideas is being tested in his laboratory now. An application of iPS cells less risky than tissue regeneration is to use cells produced from iPS cells to test drugs which are toxic, or even lethal, for certain patients but not for the majority. The idea is to take skin cells from the patient, turn them into stem cells and test the drug on those cells. Unfortunately this process requires a lot of time and money.

The normal cells are turned into iPS cells by the application of certain transcription factors. This may be done by tranferring genetic material or by using the proteins themselves directly. Originally four different transcription factors had to be combined. Recent work by Hans Schöler and collaborators indicates that one of these, Oct4, is enough in humans. The article is in Nature, 461 (2009) 649.

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