Diabetic retinopathy is one of the common microvascular complications of diabetes mellitus, which can lead to early disability. The main cause of the development of retinopathy is impaired blood circulation in the retina, which causes loss of vision in the working population. Studies of the therapeutic potential of pericytes in preclinical models of diabetic retinopathy demonstrate a wide range of beneficial effects. A promising approach in the treatment of diabetic retinopathy is the use of pericytes – microcapillary cells that have unique properties of stem cells. This study aims to activate and study the immunomodulatory and regenerative properties of adipose tissue pericytes in a model of diabetic retinopathy. To activate the therapeutic properties of pericytes, proinflammatory factors (TNF-α, IL-1β, IL-6, ICAM-1) will be used, the production of which is increased in the cells of the retina during the development of diabetic retinopathy. As a result of the study, the optimal method for activating the immunomodulatory and regenerative properties of adipose tissue pericytes will be determined to increase their therapeutic potential in a model of diabetic retinopathy.
Diabetes mellitus is an endocrine disease that includes a large group of metabolic disorders in which there are high levels of glucose in the bloodstream and impaired glycemic control. Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus and remains the leading cause of vision loss in the working-age population worldwide. In 2020, among patients with diabetes mellitus, the global prevalence of DR reached 22.27%, 6.17% of which are cases that threaten vision loss. It is currently known that diabetes causes damage to neurons, blood vessels and retinal glia, although modern clinical pathology is based on microvascular lesions. Studies have shown that all major cell types in the retina are altered during the development of DR, such as endothelial cells, neurons, microglia, astrocytes and Müller cells. The key symptom of DR is dysfunction of the vascular-nervous system. As the disease progresses, the capillaries gradually cease to perform their function, which leads to retinal ischemia and hypoxia. Most current treatments, such as laser photocoagulation, corticosteroids, vitreoretinal surgery and anti-VEGF injections, are used in the advanced stages of the disease, which is characterized by significant damage to the retina. Currently, there are very limited therapeutic options available to prevent progression from early to vision-threatening stages of DR.
The potential of regenerative therapies for the treatment of DR is currently being explored by many researchers. Various types of stem cells have been tested in preclinical models of DR, including embryonic or induced pluripotent stem cells, hematopoietic stem cells, endothelial progenitor cells, and mesenchymal stem cells (MSCs). MSCs are one of the most actively studied cell types in cellular regenerative therapy and can be isolated from various sources such as bone marrow, adipose tissue, peripheral and cord blood. MSCs secrete a number of growth factors, and their main mechanism of action is paracrine and trophic mechanisms that promote tissue regeneration. The therapeutic effect of MSCs has been studied in preclinical models, which demonstrate a wide range of beneficial effects. In a mouse model of oxygen-induced retinopathy, intravitreally injected bone marrow-derived MSCs showed beneficial effects by reducing the avascular area and neovascularization. Adipose stem cells, a type of mesenchymal stromal/stem cell derived from adipose tissue, have been shown to exhibit characteristics and express pericyte markers under certain culture conditions, including α-smooth muscle actin (α-SMA), PDGFR, and NG2. Intravitreal injection of human adipose tissue-derived stromal cells in a mouse model of oxygen-induced retinopathy promoted vascular regrowth and were able to integrate with the retinal microvasculature and localize like pericytes. It is known that pericytes support endothelial cells and play an important role in stabilizing the vascular wall at the microcirculation level. In various diseases, under the influence of proinflammatory cytokines such as IL-1β, IL-17, IFN-γ and TNF-α, MSCs become active, thereby stimulating MHC class I/II, costimulatory molecules, which leads to increased proliferative activity, survival, and enhanced immunomodulatory and immunosuppressive functions of cells. Inflammatory markers such as TNF-α, IL-1β, IL-6 and intercellular adhesion molecule 1 (ICAM-1) have been identified in high concentrations in the eyes of diabetic patients. This study plans to use these factors (TNF-α, IL-1β, IL-6, ICAM-1) to activate the immunomodulatory properties of pericytes. The immunomodulatory functions of pericytes and the therapeutic effect of activated pericytes in a model of diabetic retinopathy will be studied for the first time.
Study of the immunomodulatory properties of activated pericytes of human adipose tissue and their therapeutic potential in a model of diabetic retinopathy.
The main outcome of this project will be the development of a new strategy to increase the therapeutic potential of pericytes through their activation by cytokines for more effective treatment of diabetic retinopathy. Successful implementation of the project will allow in the future not only to increase the effectiveness of diabetic retinopathy therapy, but will also lay the methodological foundations for the use of cell-free therapy based on exosomes of activated pericytes for the treatment of diabetic retinopathy in Kazakhstan. It is expected that the results obtained will have a high socio-economic effect in the future, associated with an increase in the level of medical services provided and an improvement in the quality of life of patients with diabetic retinopathy.
The target consumers of the project results will be specialized hospitals and scientific medical centers in need of new approaches to the treatment of diabetic retinopathy.
Issabekova Assel, PhD in the specialty – 6D060700 «Biology». The project manager has 15 years of extensive experience in the subject area. H-index – 6 (ResearcherID – AAV-6961-2020; Scopus ID – 55820794800; ORCIDID – 0000-0002-8844-2510).
– Eskendirova Saule, candidate of veterinary sciences, associate professor. H-index – 6. (ResearcherID – O-2344-2017; Scopus ID – 55438123400; ORCIDID – 0000-0002-9570-7433).
– Sarsenova Madina, PhD. H-index – 6. (ResearcherID – DOJ-2648-2022; Scopus ID – 57204107549; ORCIDID – 0000-0003-1529-8471).
– Zhubanova Gulsamal, master. H-index – 1. (ResearcherID – HNG-3585-2023; Scopus ID – 57996720700; ORCIDID – 0000-0002-5476-1150).
– Kumasheva Venera, master. H-index – 1. (ResearcherID – FEX-7730-2022; Scopus ID – 57218821643; ORCIDID – 0000-0001-9240-6291).
– Shakhatbayev Miras, bachelor. (ORCID – 0009-0000-7486-5267).
2024
Human adipose tissue pericytes, which are located in the walls of capillaries and microvessels, have been isolated and characterized. According to flow cytometry analysis, pericytes have the phenotype CD73+, CD105+, α-SMA+, CD45-. The study of the differentiation potential of cells showed that pericytes are capable of differentiating into adipocytes, osteoblasts and myocytes. The immunomodulatory functions of pericytes were studied and key factors that enhance their properties in diabetic retinopathy were identified.