The role of mesenchymal stem cells along with Electric pulse in modulating the human immune system (Especially in corona disease)
The role of mesenchymal stem cells along with Electric pulse in modulating the human immune system (Especially in corona disease)
Meraj Taghi Mosleh,1,*
1. National Elite Foundation of Fars Province - Shiraz High School of Medical Sciences
Introduction: Recent developments and advances in the field of regenerative medicine have led to more uses of stem cells. Human mesenchymal stem cells, which were first obtained from bone marrow, have been used in human clinical trials due to their ease of use. But according to what mechanism do these types of stem cells work? Are they involved in immunity only through secretory factors or not? Do mesenchymal stem cells play an important role in immunity, especially against corona disease?
This idea was completely new at the time of its birth (Nowruz 1400), but taking into account the great attention paid by researchers and medical staff to this disease at the global level and the related advances and achievements, sooner or later its novelty (based on the use of MSCS) will lose. Although the nature of this idea is to pay attention to MSCS properties and use them, the presented solutions are different and new.
MSCs are derived from various sources such as bone marrow, adipose tissue, skeletal muscle, Wharton's jelly, umbilical cord, and placenta. The suppressive/modulating function of MSCs is carried out by their inhibitory effect on the cells of the innate and acquired immune system. This function is caused by the communication of these cells with immune cells in the form of direct cell-to-cell contact or through paracrine secretory factors.
The set of paracrine secretions of these cells includes various components such as growth factors, cytokines, chemokines, mediators.
It is anti-inflammatory and exosomes, so that these secretions affect the surrounding cells and cause changes in them. Many studies in animal models consider the ability of mesenchymal stem cells to rebuild and repair tissues, often instead of their proliferative properties, to be caused by their suppressive/modulating function by the same secretory factors.
Cytokines play an important role in health and disease. These molecules help the body in inflammatory and infectious reactions, repairing tissue damage and fighting some cancers. Cytokines are a group of small proteins that cause communication between two cells that are made by the immune system and act as a chemical messenger. Cytokines are proteins, peptides or glycoproteins that are secreted by lymphocytes or monocytes and regulate immune responses, hematopoiesis and maturation of lymphocytes.
B and T lymphocytes are very important in regulating immune responses. Based on the results of various studies, the effect of MSCs in acquired immune responses is mostly exerted through T lymphocytes, but nevertheless, MSCs can stimulate B lymphocytes through cell-to-cell contact and by releasing soluble factors. to influence
The response of T lymphocytes to MSCs can be expressed in three cases, which include inhibiting the proliferation of T cells stimulated by many stimuli, regulating the production and secretion of cytokines (pro-inflammatory and anti-inflammatory) from these cells, and affecting the differentiation of different subtypes of T cells. In particular, the induction of regulatory T lymphocytes (Treg) type 1 (TR1) and expressing
Foxp3 (Foxp3+ Treg). On the other hand, in an inflammatory environment, the response of innate immune cells to MSCs will also lead to an acquired immune response. Therefore, through the modulation of innate immune cells, these cells have indirect regulatory effects on T lymphocytes and especially on B lymphocytes (Hosseini et al., 2019).
There is evidence that mesenchymal stem cells, by reducing the expression of MHC-II, CD11 and CD83, stop the activity of macrophages and reduce the secretion of pro-inflammatory cytokines such as TNFα and IL12. Stopping T lymphocytes in the G0/G1 phase of the cell cycle and also reducing the secretion of pro-inflammatory cytokines TNFα, IL6 and IL17 are other effects of MSCS on the human immune system (Weiss and Dahlke, 2019; Golchin et al., 2020).
Many studies have been conducted in relation to inhibiting the proliferation of T lymphocytes, because inhibiting the proliferation of these cells is the most important function of MSCs in the laboratory environment. For example, MSCs can inhibit the proliferation of T lymphocytes stimulated by polyclonal mitogens and alloantigens, as well as the activation of T lymphocytes by CD3 and CD28 antibodies. In addition, it has been reported that exposure of Treg cells to MSCs in co-culture significantly increases their immunosuppressive ability. These results indicated that programmed cell death receptor interactions may be responsible for the increased suppressive ability of Treg cells exposed to MSCs. However, it is noteworthy that the depletion of Treg cells from the culture medium has no effect on the suppression of T lymphocyte proliferation by MSCs, because It seems that MSCs prevent the physical contact of T lymphocytes with antigen presenting cells (APCs) in an unknown way. Although a specific molecular mechanism has not been identified in this field, there are hypotheses in this regard.
T cells provide
For example, it has been suggested that Treg cells strengthen the interaction of T lymphocytes with low affinity to APCs by reducing the probability of T lymphocytes separating from APCs, and thus regardless of whether the cells are tolerant or responsive. Treg stabilizes the immune status (Hosseini et al., 2019).
On the other hand, MSCs are involved in regulating the production and secretion of cytokines from T lymphocytes. Many reports in this regard show that MSCs reduce cytokine secretionpro-inflammatory and increased production of anti-inflammatory cytokines IL-10 and
IL-4 from activated T lymphocytes play a role. Also, MSCs can produce suppressive molecules such as IDO, PGE2, TGF-β, nitric oxide (NO), heme oxygenase 1 (HO1), leukemia inhibitory factor (LIF), apoptosis, liver growth factor. (HGF) and galectins have a direct effect on T cells.
Mesenchymal stem cells can be very important in the treatment of diseases such as multiple sclerosis, colorectal cancer and corona.
Multiple sclerosis is an autoimmune disease of the central nervous system in which progressive destruction of the myelin sheath is observed. In their interaction with the innate immune system, MSCs exert their regulatory effect on the immune system. This type of stem cell secretes anti-apoptotic molecules and neuron growth in order to protect neurons in nerve damage. According to various studies, MSCs apparently play a role in repairing damaged tissues in this disease. B and T lymphocytes play a role in the development of autoimmune diseases, and as mentioned earlier, MSCs have a regulatory effect on these lymphocytes and with their functional mechanisms (secretion of cytokines and direct cell-cell contact) can play an important role in the treatment of MS.
Based on the studies, the fourth most common cancer leading to death is colorectal cancer (CRC), and in the targeted treatment of this type of cancer, research is focused on MSCs. MSCs are cells with high division ability that are not completely differentiated, and one of the characteristics of these types of cells is their tendency to form tumors. However, these cells are used as carriers to deliver drugs to the primary site of the tumor, and there are studies that show the potential of MSCs to destroy the tumor by inhibiting tumor cell proliferation and inducing apoptosis. are, of course, taking into account the important point that when MSCs are in contact with pathogenic agents, their secretions, proliferation and differentiation are affected. According to studies, MSCs derived from adipose tissue stimulate and increase tumor growth and cancer metastasis. Also, MSCS can be oncolytic virus carriers. This type of virus has two types of anti-tumor activity, which includes anti-cancer activity and stimulation of the body's immune system. Stimulation of the immune system is done by initiating an acquired anti-tumor response against cancer epitopes (part of cancer antigens).
Today, the corona disease has become a global problem that has taken the lives of many people and has had various mutations. As you know, this virus has a great impact on a person's lungs and lungs, and by multiplying in this organ and other parts of the body, it affects the respiratory system and, in some cases, blood circulation, and as a result, they suffer disrupts Due to the speed of mutations of this virus, it is not possible to market a suitable and definite vaccine with the desired expected performance. Because these mutations, over time, can reduce the efficiency and effectiveness of the vaccine, and if during the mutation, a large part of the antigenic form of the virus changes, against the mutated type, the vaccines will be significantly less effective. And they will lose their effect. Therefore, we must look for another solution besides the vaccine.
Mesenchymal stem cells can be used to help solve this crisis! Based on the characteristics and effects of these cells on the immune system, they can be used to fight the virus from the moment it enters the body. Regarding the functions of MSCS, Dr. Hossein Baharond, Royan Research Institute and Kerman University of Medical Sciences mentioned the therapeutic properties of these cells and the type derived from the umbilical cord. These centers have announced that MSCS play an important role in improving the complications of Corona and dealing with this disease by improving and repairing the degenerated tissue, and by emitting electric pulses in the environment, it should be checked whether MSCS is present in the mentioned diseases. They increase the speed of treatment or not?
Methods: In order to investigate the effect of viruses and mesenchymal stem cells on other changes, in each sample (lung tissue cells,
T, B lymphocytes and natural killer cells (phagocytes), the test is summarized in six samples. In this way, I found out what effect each one alone would have on lung cells and the mechanism of MSCS effect on zinc. In the experiment in question, the basis was Shiraz, in cooperation with the University of Medical Sciences, in the safety level 3 laboratory and to achieve the results.
More precisely, it should be done with three repetitions. But due to the lack of full facilities to work with such a dangerous virus, and high costs, the experiment was not carried out. In this way, the plan to defend the plan was written and presented to the university, and instead, a project on the validity of the collaboration and acceptability of the idea and research carried out by Borji Mohammad Rasulullah of Medical Sciences of Shiraz University was approved.
Further, if MSCS has such a feature and mechanism, it should heal naturally without humans, but due to the relatively slow and late action speed, such an event cannot decide whether to increase phagocytes and MSCS. undertook
In addition to the above, electrical pulses play a role in cell migration and proliferation. The effect of these pulses can be seen on the cells at a voltage between 0.5 and 2 volts and for half an hour to two hours. Also, based on the research conducted (Cen Chen, Xue Bai,...), movement can be used as a tool to regulate the behavior of cells and tissue engineering, which is important in calling MSCS to the treatment site. gave performs Although they investigated the effect of electrical pulses on the normal function of viruses, cells, tissues and surrounding organs, but in general, this design can be useful in treatment.
Results: Mesenchymal stem cells have diverse and extensive potentials, which with the advancement of science and the increase of people's knowledge and awareness of it, more features are discovered and more uses are made of it in the field of treatment. According to the research, the anti-inflammatory property of MSCS interferes with the activity of the corona virus. As you know, the immune response and inflammation are regulated by inflammatory cytokines (TNF), increasing the secretion of these substances, with positive feedback, can increase inflammation and worsen the patient's condition. Cells infected with the virus secrete a protein called type 1 interferon in response to the entry of the virus
they do. In the secretion of this type of interferon, a protein called mitochondrial antiviral messenger protein (MAVS) is involved.
Mesenchymal stem cells affect lymphocytes in two ways, cells that are the most important in specific defense and play an important role in fighting viruses and other pathogens. Secretion of paracrine agents and cell-to-cell contact are also among these methods. The paracrine secretory complex includes exosomes, chemokines and the most important of them, cytokines. The most important feature of MSCS is not having a receptor for corona virus and AIDS. This feature means that the corona virus is able to enter this type of cell and destroy it.
During the research and the results obtained, showing the positive effect of MSCS in repairing the tissues damaged by the virus
is. Also, these cells control the secretion of pro-inflammatory and anti-inflammatory cytokines and thus control the inflammation caused by the activities of the virus. The presence of a sufficient amount of MSCS can be effective in the process of dealing with the virus, and considering that the mentioned research, due to the lack of possibilities and costs, has changed from an experimental mode to a research and questionnaire in Shiraz University of Medical Sciences. A definite result of MSCS's direct confrontation with the coronavirus cannot be provided. However, with the presence of more and more mesenchymal stem cells in the area infected with the virus, not only the inflammation is controlled and can save the patient from death, but with its secretions, it can indirectly fight the corona virus. also pay For example, one can pay attention to the statistics of deaths caused by Corona; This statistic is higher in adults than in teenagers, and the lower the age, the lower the statistics will be seen. Here, we can mention the continuous and more active presence of MSCS in teenagers and younger ages as one of the factors of reducing mortality. As you know, with increasing age, the successive division of cells will decrease and as a result, the number of mesenchymal stem cells will decrease and old samples will remain. As a result, it can be mentioned that along with other relevant factors, with the decrease in the number of MSCS, the repair and anti-inflammatory activity and the mentioned mechanism have decreased and as a result the death rate has increased.
Conclusion: Acquired or adaptive immune cells that increase stem cells in body blood fluids to accelerate the healing process of tissue damage and infectious diseases are influenced by MSCs.
Many innate immune cells, including macrophages, neutrophils, mast cells, suppressor cells derived from myeloid stem cells, and natural killer cells exist in inflammatory sites and can be regulated by MSCs. For example, MSCs, by producing immunosuppressive molecules and metabolites such as prostaglandin E2 (PGE2), a protein called TNF-stimulated gene (TSG6), lactate, kynurenic acid and spermidine, can change the characteristic of macrophages from pro-inflammatory phenotype. change to an anti-inflammatory phenotype, which is a very important mechanism in the processes of corona disease.
The functional mechanism of mesenchymal stem cells (MSCs) is carried out by communicating with T, B, and natural killer cells with the help of paracrine secretory factors and direct cell-to-cell contact, and plays a role in the activity of lymphocytes.
T lymphocytes are one of the most important agents of the body's immune system, which MSCs affect in three ways, including inhibiting the proliferation of T lymphocytes, releasing pro-inflammatory and anti-inflammatory cytokines, and inducing regulatory and expressing T lymphocytes.
is. Also, in autoimmune diseases such as MS, MSCs play an essential role due to their regulatory effect on T lymphocytes and their secretions, and researchers hope to be able to use these MSCs in the treatment of MS.
Mesenchymal stem cells are a very important factor in colorectal cancer (CRC). The function of MSCs has significant effects in both healing and aggravating the cancer. These cells can stimulate and grow cancer tumors (in the type derived from adipose tissue) and against this feature, they can carry drugs and prevent tumor proliferation. Also, mesenchymal stem cells are very important in corona disease. These cells, in addition to treating corona indirectly (with the help of proposed functional mechanisms), play an important role in improving the complications caused by the disease.
Also, according to the studies and scientific model, it can be concluded that mesenchymal stem cells will have more continuous activity in the presence of electric pulses and electric pulses play an effective role in calling these cells to a specific tissue of the body. This can have wide-ranging effects and treat various diseases in the field of medicine, including the mentioned diseases and today's global problem, Corona. Finally, with the help of this project, we can have the vision to control diseases and some of today's medical challenges.