02 June 2014

About the present and the future of IPSK – first-hand

New life of old cells gives hope

Yulia Smirnova, "Science and Life"In 2012, Shinya Yamanaka, along with John Gardon, received the Nobel Prize for the discovery that mature cells can be "reprogrammed" back into a stem pluripotent state.

The method of converting mature cells into stem cells appeared six years before the award, in 2006, after which everyone immediately started talking about the broadest prospects opening up to medicine and biology. Professor Yamanaka spoke about the future of the method and about the research conducted at the Center for the Study and Application of Induced Pluripotent Cells (Center for iPS Cell Research and Application) in Japan, led by him, at an open lecture held on May 29 at St. Petersburg Polytechnic University.

In his youth, the future Nobel laureate wanted to become a doctor. He received a medical degree and a doctorate in medicine, and even managed to work as an orthopedic surgeon. But later, Shinya Yamanaka decided that he would be more useful if he started doing science. In 1998, James Thomson and his collaborators from the University of Wisconsin-Madison obtained for the first time a line of human embryonic stem cells (ESCs). The potential of stem cells for use in medicine was immediately assessed by scientists: if it were possible to replace the affected cells and tissues with new ones grown from stem cells, then it would be possible to solve the problem with a number of serious diseases. However, there was an ethical problem – after all, ESCs can only be extracted from human embryos.

A year later, Yamanaka started studying stem cells at the Nara Institute of Science and Technology (Japan). He decided to answer the question: if almost any cell of the body can be obtained from a stem cell, is it possible to force a mature, specialized cell to turn into something else? The scientist believed that the search for a mechanism that could force the cell to be reborn would take the rest of his life. However, after 6 years, he and his colleagues received the results, which were soon awarded the Nobel Prize.

The method of producing induced pluripotent stem cells (iPSCs) has been improved since 2006, and now, for example, some blood cells taken from a simple clinical sample can be reprogrammed. Moving from theory to practical use of technology, the professor demonstrated amazing shots: a pulsating tissue appeared on the screen. This, as Yamanaka explained, is the tissue of the heart muscle, which was grown in the laboratory from a single blood cell converted into a stem state.

To date, there are three main areas of use of IPSC. The first is in vivo, in cell therapy, when old diseased cells are being replaced with new, differentiated and healthy ones. The second is in vitro, when different types of specialized cells are obtained from iPSCs for testing various pharmacological drugs, drugs, toxins, etc. The third direction is the creation of a bank of human tissues with various genetic defects to study and find ways of possible treatment of genetic diseases.

It is known that some antibiotics and painkillers as a side effect cause arrhythmia, which in severe cases leads to death. With the help of IPSC, antiarrhythmic drugs can be tested more thoroughly, because to test the toxicity and safety of the drug on the heart muscle, you do not need to extract cells directly from the human heart, they can simply be grown in the laboratory. Now for such tests, cancer cells are also used, in which the gene encoding the cellular potassium pump is activated – this pump is necessary for the work of the heart muscle. Thus, it is possible to study the potassium permeability and the internal physiology of the cell in response to the action of a particular component of the drug.

Another illustrative example is amyotrophic lateral sclerosis (ALS), in which progressive damage to motor neurons occurs, accompanied by limb paralysis and muscle atrophy. One of the most famous ALS patients is cosmologist Stephen Hawking.

The institute headed by Professor Yamanaka managed to obtain iPSCs of healthy people and patients with ALS. No differences were found in the stem cells themselves. But after these cells turned into motor neurons, the differences were found. It turned out that the processes of neurons in ALS patients were two times shorter than in healthy people. Now, substances that may be able to reverse the process of shortening of neural processes are being tested on neurons grown in the laboratory.

The third way to use IPSC is the very thing that once prompted the scientist to take up stem cells, cell therapy. Scientists see great prospects in using iPSCs for post-traumatic spinal cord repair, when damaged cells are replaced with new healthy ones. Successful experiments on mice allow us to hope that in a few years this method can be tested on humans.

Clinical studies on the use of IPSC in the treatment of retinal degeneration, one of the causes of senile blindness, will begin at the end of 2014. Since the eye is very convenient to observe, in the course of this study, scientists hope to solve another question. There are serious concerns that iPSCs are not completely safe, as they can go the wrong way, turning into cancer cells instead of normal specialized cells. It is very convenient to observe the retinal cells, and if at least one cell tries to form a malignant tumor, it can be immediately noticed and the "renegade" can be removed using a laser. However, Professor Yamanaka believes that although concerns about cancer are justified, the risk of such deviations is minimal, and the benefits of using IPSC in clinical practice will be undeniably greater than the potential harm.

Another problem that can be solved with the help of IPSC is the shortage of donated blood. The professor cites Japan as an example, where in recent years there has been a noticeable aging of the nation and people are increasingly requiring blood transfusions. New technologies can provide clinics not only with a sufficient amount of blood, but also with individual types of cells.

Returning to the replacement of diseased cells with healthy ones, one more advantage of IPSC should be mentioned. The usual headache of transplantologists is the rejection of transplanted tissues, but with IPSC, you don't have to worry about this – after all, the source material will be taken from the patient himself, and the cells obtained from IPSC will be "his own" for his immunity. However, such technologies are still not too cheap and require a lot of time to perform, but in the case of acute conditions, sometimes the bill goes for days and hours.But it turned out that this problem can be solved if we use not only our own cells to obtain iPSCs, but also donor cells suitable for the main histocompatibility complex (HLA, from the English "Human Leucocyte Antigens" – human leukocyte antigens).

HLA antigens play a crucial role in regulating the immune response to foreign antigens and are themselves strong antigens. According to them, immunity determines "own" and "strangers", and the discrepancy between the donor and the recipient according to HLA leads to rejection of transplanted organs. In total, there are more than 100 types of such antigens. It turned out that in the case of IPSC, the donor can be a person homozygous for a certain type of HLA, and the recipient is heterozygous, that is, it is not necessary to look for an absolutely complete immune match. Finding a sufficient number of potential donors, even in a small Japan, is a huge deal. According to the professor, this should be a large-scale action, in which most of the country's residents will take part. But if only 140 homozygous donors can be found, this will be enough to provide IPSC to 90% of the population.

Portal "Eternal youth" http://vechnayamolodost.ru02.06.2014

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