XVI Международная студенческая научная конференция Студенческий научный форум - 2024

РОЛЬ Relevance

Despite the annual improvement of methods to combat pathologies of various types, some diseases are still poorly treatable or not treatable at all. It is precisely such diseases that threaten the health of the population, and it is on them that the main forces of the research groups responsible for developing innovative treatment methods should be focused.

Among diseases of this type, pathologies of the cardiovascular system occupy a special place since they are the main cause of death worldwide. According to the World Health Organization, in 2021, about 17.9 million people died from cardiovascular diseases, which accounted for 31% of all deaths in the world, and 85% of them were deaths from acute myocardial infarction or stroke.

Since 1972, Russia has been ranked first in terms of the number of deaths associated with pathologies of the cardiovascular system, since the annual figure exceeds the value of 900 thousand people per year.

That is why the development and study of the ability to regenerate heart tissue is one of the main tasks of modern scientists.

PURPOSE AND METHODS

The aim of the work is to study and evaluate the significance of the immune response and the action of the immune system to stimulate the proliferation of cardiomyocytes in patients with myocardial infarction by analyzing scientific articles on the topic.

PROGRESS OF WORK

Myocardial infarction is one of the most common and clinically significant heart diseases that occurs when the coronary artery is blocked and blood flow through the collateral vessels is impossible due to atherosclerotic lesion of the latter. It is a process of cardiomyocyte death, preceded by dystrophy and necrobiosis.

In most cases, the localization of myocardial infarction is the left ventricle and interventricular septum.

There are three main stages in the pathogenesis of myocardial infarction. The first stage is ischemic, lasting about a day and characterized by the development of lesions in areas of insufficient blood supply. During this stage, when using the method of polarization microscopy, excessive contraction of myofibrils is observed in the foci of ischemia. The second stage is necrotic, characterized by the formation of a necrosis focus. The third stage is the stage of scarring of the formed lesions, which is characterized by subsequent hypertrophy of cardiomyocytes of a normally functioning myocardium, which continues until adequate contractility is achieved.

Thus, the main strategy for the regeneration of cardiac tissue after myocardial infarction is to induce endogenous proliferation of cardiomyocytes, which can be triggered by the human immune system.

The immune system is fundamental to tissue homeostasis and is the first line of defense after various infections, injuries, or diseases. In a damaged heart, a large number of immune cells move to the site of damage.

GPCM macrophages, for which the pericardial cavity serves as a reservoir, play a key role in the formation of the immune response, and, as a result, ensuring the regenerative ability of cardiomyocytes.

GPCMS differ transcriptionally from neighboring cardiac macrophages. A characteristic feature and marker of these peritoneal macrophages is GATA6, which is considered to be the leading transcription factor.

The mechanism of GATA6 mobilization and the method of its investigation are complex. First of all, an experimental model of myocardial infarction using the coronary ligation method was used to determine the further fate of these cells of myeloid origin. After a certain period of time, a rapid reduction in the number of GPCMS was noted, associated with a large flow of neutrophils and monocytes into the pericardial cavity. After the damage, all three cell types returned to normal values. It is based on this approach to studying the migration ability of this type of macrophages that we can indirectly conclude about their migration ability and increased activity in case of damage to cardiomyocytes, primarily occurring in myocardial infarction.

There are several studies that have shown that retinoic acid is a key inducer of GATA6 expression, which is also necessary for the maturation of migrating monocytes into peritoneal and pericardial macrophages.

The subsequent mechanism of operation of a special group of macrophages is also under investigation. To directly track the activity and ability to change the phenotype of the surrounding cell ensembles, the method of fluorescent labeling is used, which is achieved by providing intercostal access to the pleural and pericardial cavities.

In general, macrophages are crucial for recovery from injury. During tissue repair, macrophages can exacerbate ischemic damage by disrupting the microenvironment and metabolism and causing cell death. On the other hand, cytokines such as vascular endothelial growth factor-α (VEGF-α), insulin-like growth factor-1 (IGF-1) produced by macrophages contribute to the proliferation of various cells.

From the point of view of regeneration and restoration of the heart, the functions of macrophages can be divided into three main categories. First, macrophages can stimulate the proliferation of endothelial cells, smooth muscle cells, and fibroblasts by releasing growth factors and stimulating angiogenesis for tissue repair. In a study by Fantin et al. It has been shown that macrophages of the heart tissue are involved in the formation of capillary networks in the myocardium, which can be mediated by signaling. After that, macrophages can work as chaperones in the fusion of cells targeted by vascular endothelial growth factor (VEGF). Moreover, it has been reported that macrophages can differentiate into endothelial cells or endothelial precursors.

Macrophages can be classified as resident or originating from monocytes. These two types of macrophages also perform different functions. Normally, both resident and monocyte-derived macrophages are present in the hearts of newborns and adults, but their subtypes and numbers differ. The hearts of newborns, which can renew themselves, will selectively increase the permanent population with a slight increase in the number of cells originating from monocytes.

On the contrary, the hearts of adults contain an increased number of macrophages originating from monocytes, although the percentage of resident cells is initially the same as in newborns. In cardiomyocyte ablation experiments, it was found that resident macrophages can cause less inflammation and promote cell proliferation and the formation of new coronary vessels, while macrophages derived from monocytes have only an inflammatory effect.

Initially, these macrophages lead to the acquisition of an inflammatory phenotype in the thickness of damaged cardiomyocytes, release cytokines with anti-inflammatory effects, and remove dying tissues. Then, the regenerative ability of cardiomyocytes is stimulated, leading to the replacement of heart muscle cells with new ones capable of normal contractile activity. ^[8]

It was also shown that macrophage amplification after injury in newborn mice occurred quickly, in no more than 5 days, while inflammation and recovery tended to occur more slowly in adult hearts. However, since macrophages originating from monocytes can make up for the loss of resident cells, the differences between responses to damage in the hearts of newborns and adults require further study to clarify the mechanisms.

In addition to the work of the macrophages themselves, the so-called SCS (heart stem cells), which carry out their mechanisms of action in tandem with other cells of myeloid origin, are also included in the work on heart regeneration.

The revealed ability of MMSCs to differentiate in the cardiomyocytic direction was further studied when they were introduced into the bloodstream during experimental MI in laboratory animals. Histological analysis of the infarction zone revealed CMCs with a donor label that expressed α-actinin, troponin-T, tropomyosin, heavy chains of myosin and connexin-43. MMSC transplantation into the infarction zone led to a significant improvement in the functional parameters of the damaged myocardium. It was also possible to show that the introduction of MMSC caused increased angiogenesis due to increased endogenous production of vascular endothelial growth factor VEGF. Thus, the unique properties of MMSCs were demonstrated: the ability to migrate to the infarction zone from the bloodstream, differentiate into contractile CMCs, and produce factors stimulating neoangiogenesis. The issues of graft survival and electrical association with the recipient's CMC remained to be resolved.

At the present stage of research, it has been established that polypotent stem cells are resident (or can be formed as a result of differentiation) in all organs of the adult body. When stimulated by growth factors, they replace cells that die by apoptosis.

A few decades ago, it was widely believed that CMCs were unable to enter mitosis. Differentiating soon after birth, CMCs persist throughout life. Starting from 7 months after birth, they do not proliferate, and hemodynamic stress causes only hypertrophy of the heart muscle. A factor limiting the proliferation of CMC is the presence of strictly oriented aggregates of contractile proteins – myofibrils, which interfere with the processes of cytokinesis. In myocardial pathology, in particular ischemia, as a manifestation of an adaptive compensatory reaction, excessive polyploidy by incomplete mitosis is noted, which results in the appearance of single-core tetraploid, double-core diploid, polytene CMCs. This phenomenon is associated with a sharp decrease in contractile myofibrillary protein per genome, thinning and elongation of CMC and a decrease in myocardial contractility, diagnosed by a change in the cardiac index. ^{[14, 15]}

Conclusion

During the study, it can be concluded that the immune system, namely macrophages, play an important role in the restoration of the heart muscle.

Pericardial cells migrate to the heart in response to injury, contributing to accelerated proliferation of cardiomyocytes and, as a result, regeneration of cardiac muscle tissue.

It is worth noting that the discovery of such an action of macrophages has enormous clinical significance, since during heart surgery, the pericardial fluid or the entire pericardial sac is often removed, which can slow down the proliferation of cardiomyocytes and, as a result, further treatment.

The regenerative potential of resident stem and progenitor cells of the heart has recently been an actively developing area of cell therapy for acute and chronic heart diseases. The development of this area is associated both with the difficulties of using non-resident stem cells, and with the discovery of a variety of types of resident cells that have a protective, immunomodulatory, anti-inflammatory and fibrosis-suppressing effect, which is the basis for the reparative ability of the heart muscle after injury. Stem and progenitor cells of the heart induce angiogenesis in the heart muscle, the formation of new cardiomyocytes, endothelial and smooth muscle cells.

The analysis of the results of the conducted studies allows us to conclude that the stem and progenitor cells of the heart have a positive, long-lasting effect. However, the low content of these cells in heart tissues, as well as the difficulties associated with their in vitro cultivation and targeted delivery to damaged areas of the myocardium, currently limit the use of resident cells for therapeutic purposes.

The rapid development of cellular technologies and new therapies opens up prospects for the use of cardiac stem and progenitor cells. It is assumed that future regenerative approaches can combine genetic engineering, the inclusion of various stimuli (mechanical, electrical and biochemical factors) in therapy and approaches to tissue engineering to develop a carefully controlled system that will increase the regenerative capacity of resident stem and progenitor cells of the heart, and which can potentially be applied not only in therapy, but also in disease modeling and drug screening. ^[16]

With continued research in this area, new directions in therapy may appear, which may contribute to reducing the percentage of deaths from myocardial infarction both in Russia and around the world.

List of used literature:

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