Regenerative biomedicine
Interview with Anastasia Efimenko
Anna Posokhova, "Scientific Russia"
What do we know about regenerative medicine? For sure, many people think that this is rather something from cosmetology. But no. To date, methods of regenerative medicine are actively used in diseases and injuries, especially when the chances of not only recovery, but also survival are low, when other methods of treatment have already exhausted themselves. These are special therapeutic approaches that allow to restore damaged or diseased tissues, for example, with the help of human and animal stem cells. Although the direction is modern, it has been in medicine for almost 25 years and continues to develop actively in many countries.
"Scientific Russia" in an interview with Anastasia Yurievna Efimenko, Candidate of Medical Sciences, head of the Laboratory of Tissue Repair and Regeneration of the Institute of Regenerative Medicine of the Medical Research and Educational Center of Lomonosov Moscow State University, learned what innovations have been developed in the field of regenerative medicine, and what is its uniqueness in medicine in general.
– Is it possible to say now that regenerative medicine is a new branch of medicine in general? And how much will it improve the health of patients?
– Regenerative medicine today is not so much an industry, but a new medicine in general. Regeneration is the ability of living organisms to restore lost and damaged tissues and organs. Until recently, medicine with the help of drugs had an impact on the function of cells, mainly suppressing adverse processes and contributing to the treatment of diseases.
The possibilities of medicine in terms of restoring lost and damaged tissues, growing new structures – it was only a dream. To date, we have reached it.
Regenerative medicine is based on absolutely unprecedented successes of biologists, chemists and doctors, as well as specialists in developmental biology. Today it is more correct to say not regenerative medicine, but regenerative biomedicine. Interdisciplinary fields are very closely connected in it, which help each other to understand how tissues and organs can be renewed and restored in case of damage and diseases, as well as how this knowledge can be implemented in the form of therapeutic approaches.
The need for this is huge. Almost all severe diseases are associated with irreversible damage to the unique functions of various tissues and organs. The task of regenerative medicine is to learn how to replace them, and ideally, to understand how the body itself copes and help it. In this sense, it is fundamentally different from all other areas: both clinical medicine and medical science.
Regenerative medicine explores universal mechanisms that are implemented in all tissues and systems of the body. Understanding these universal mechanisms with the help of one successful discovery will allow us to come up with new approaches to the treatment of diseases of various organs and systems.
– How is the process of tissue regeneration with the help of stem cells?
– The main cellular workers responsible for replacing dead or lost tissue cells are stem cells. They are found in all tissues, but differ in their potency. Currently, many different types of stem cells are described. Some of them can be isolated from the human body from a variety of tissues into culture.
One of the key tasks of regenerative medicine is to study the properties of stem cells and the conditions for their successful functioning. The practical result of such studies is an attempt to use these cells, unique in their properties, as a cellular preparation for introducing them into the tissue where replacement is needed, and launching into the process of differentiation – specialization into the desired tissue types. This is not an easy task.
Initially, huge expectations about the success of such approaches of regenerative medicine in many ways did not justify themselves. Now we are witnessing such a kind of "rollback" back, as it became obvious that we need to better understand how stem cells function and how their unique properties can be used. In this sense, it is important to rethink the concept of regeneration from the point of view of the action of a non–stem cell separately, since in the body itself (this has already been shown in a number of very serious studies) any stem cells exist in a special environment - a microenvironment called a stem cell niche. This is a very specialized set of different cellular, matrix, signaling components, small molecules that control the function of stem cells. On the one hand, they allow it to preserve the properties of stemness, on the other hand, when activated, when damaged, it is necessary to correctly interpret the signal and start the differentiation of the stem cell in the right direction.
– Is it possible to restore part of the work of the brain after severe damage?
– The brain has its own stem cells – neural stem cells. They are activated when damaged, but this is often not enough. This tissue is so complex and the interactions between cells are so complex that the restoration of cellular composition in itself does not mean the restoration of organ function.
To date, approaches to obtaining neural cells are being actively developed, for example, for the treatment of Parkinson's disease – specific dopaminergic neurons. They learned to get them from stem cells of a special type. But their ability to differentiate is much lower than that of embryo cells. This is a problem that significantly limits the possibilities of drug development.
However, in 2006, a discovery was made – specialized cells can be "rolled back" to the embryonic stem state by introducing several genetic constructs with transcription factors regulating the genetic program. These are induced pluripotent cells. From such cells, neurons of various types and other cells of nervous tissue are now well learned in the laboratory. Many studies are being conducted in an attempt to use these approaches for the treatment of neurodegenerative diseases. Interesting directions are being developed related to the treatment of post-stroke conditions in an attempt to limit damage, contributing to the improvement and restoration of brain tissues.
At the Institute of Regenerative Medicine of the IOC and at the Faculty of Fundamental Medicine Moscow University is also conducting such developments. On the one hand, they are aimed at finding factors that critically affect the function of neurons, which can be introduced as a genetic construct – gene therapy (a direction of regenerative medicine that involves the introduction of certain genes that control the function of cells and allow creating locally good expression of the desired factor contributing to the survival of neurons). On the other hand, an attempt is being made to find a complex of factors affecting different types of cells in the brain. And when they are introduced, they contribute to the restoration of the microenvironment of neurons for survival or stimulation of neural stem cells in case of damage, so that they replace the lost neurons and contribute to the establishment of new connections between neurons in the brain.
– How does cell therapy work? What is its uniqueness?
– Cell therapy is one of the main directions of regenerative medicine. Its tasks – stimulation, restoration of the structure and function of damaged or lost tissues are largely realized due to the action of cells as drugs of a fundamentally new type. Here cell therapy can be considered even wider than regenerative medicine. To date, her outstanding achievements in terms of using living cells isolated from some source as a therapeutic agent have shown themselves very well in oncohematology. In recent years, several drugs based on the use of T-lymphocytes have been registered, which have been taught to recognize a tumor with the help of genetic engineering. And in oncohematology, we have achieved unprecedented success in the treatment of severe leukemia.
Now many teams, including in our country, are actively working with cells with chimeric antigenic, T-cell receptor (CAR-T) in order to teach them to recognize solid tumors. This task turned out to be more difficult. Nevertheless, there are successes in this area. It can be expected that cell therapy will occupy its niche not only in oncohematology, but also in other areas of oncology.
If we talk about regenerative medicine, then there is one direction that has been implemented in cell therapy for a long time – bone marrow transplantation. Now we have this cell therapy technology that saves many lives every year in real practice.
Most modern cellular preparations are based on the use of hemapoietic stem cells, since they are easier to obtain and modify in the right way. For example, by changing a genetic defect that leads to the development of anemia or some severe immune disease, you can correct these cells and simply return them to the bloodstream, so that their descendants will already be healthy.
For the restoration of other tissues, cell therapy is also an excellent approach, only much more difficult to implement. It is necessary that the cells introduced from the outside reach the target tissue and the target organ, integrate there and get into the microenvironment that will allow them to work. Unfortunately, this does not always happen. In this sense, the source of cells for cell therapy is an important issue.
Now, based on the understanding of how cells interact with each other, another interesting branch of cell therapy is developing – cell therapy without cells. This is the use of a complex of signals secreted by a specialized type of cells (stem cells or their descendants). The complex of these signals, or the secret of cells, can be used as a therapeutic agent. In this case, we get rid of various risks associated with the introduction of living cells into the body. It is possible to develop a complex of these signals in large quantities at once, standardize it, test it for safety and then use it as a drug.
Cell therapy without cells is also actively developing now. So far, its prospects in different directions are only being explored. But this will become one of the sections that allows you to simulate regenerative signals and thereby stimulate your own endogenous potential of tissues to restore and recreate the structural, functional complex of the necessary processes for human health.
– What latest developments are ready to enter into practice?
– We need to be quite careful here, since regenerative medicine is not just another approach that will allow us to offer a new pill for anything. No! This is working with completely new objects that affect the very essence of the structure of the human body: on the cellular composition of tissues, on the genetic program of cells and on the interaction of organ systems with each other.
It is not for nothing that the Institutes of Regenerative Medicine are localized in medical centers, because the translation of such developments is certainly the most important task for us.
One of the interesting directions of our laboratory is the research and development of approaches to the directed regulation of stem cell niches, since this allows you to regulate tissue regeneration from the inside due to the complex influence on various components of the niche that controls the function of stem cells. For one of these drugs, we are finishing preclinical studies this year, and we are preparing documents for clinical trials.
It is also important to understand why, with many injuries, tissue regeneration does not occur or is insufficient. And I must say that in most of our tissues and organs, healing is realized not so much through full-fledged regeneration and restoration of tissues, as due to the rapid "patching" of the defect and the development of a connective tissue scar in this place.
Fighting this imbalance when fibrosis occurs instead of regeneration (especially in vital organs – heart, lungs, kidneys) – this is one of the very interesting tasks that we are trying to solve now. We focused on lung fibrosis, because there are serious diseases associated with it that are practically not treated. We tried to study how cell differentiation is involved in this progression of unstoppable fibrosis in chronic lung injury, and found a subclass of stroma cells that are able to regulate this process by transferring special signals to cells involved in the development of the fibrous matrix, called myofibroblasts. They are focused on the production of many components of the connective tissue matrix.
There is a certain subtype of cells in the stroma that secrete signaling non-coding microRNAs, which are in small vesicles (vesicles) they are transferred to myofibroblasts and are able to influence the genetic program, stopping their transformation into cells secreting a lot of matrix.
The use of such bubbles with the necessary microRNAs or the microRNAs themselves in a complex, which according to the results of research will be shown as an effective regulator, and may become a therapeutic approach for the treatment of fibrosis. The results of these data were obtained on animal models. If it turns out that in humans, these approaches can not only stop the progression of lung fibrosis that has developed as a result of infectious and other lesions, but also lead to the treatment and restoration of at least part of the functional tissue, then this will allow us to create unique drugs and bring them into clinical practice.
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