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616-092
К 43
Кирик, Віталій Михайлович.
Патогенетичні механізми реалізації регенеративного потенціалу соматичних стовбурових клітин з урахуванням критеріїв їх якості та ефективності [Текст] : автореферат дис. ... д. мед. н. : 14.03.04 / В. М. Кирик ; Буковинський державний медичний університет, 2024УДК:
Анотація: У дисертаційному дослідженні встановлено механізми реалізації регенеративних ефектів соматичних стовбурових клітин з жирової тканини, плаценти, тканиноспецифічних ендотеліальних та кардіальних прогеніторів на моделях пошкодження серцево-судинної системи та кісткової тканини у мишей з врахуванням комплексних критеріїв їх якості та доклінічної ефективності. Продемонстровано переваги тривимірних трансплантатів із спрямовано диференційованими стовбуровими клітинами для покращення регенерації тканин різних типів. Вперше встановлено вплив вікової дисфункції ніші стовбурових клітин на їхні морфофункціональні властивості. При трансляції результатів експериментальних досліджень у клініку вперше підтверджено безпеку та ефективність інтраміокардіальної трансплантації стовбурових клітин плаценти у пацієнтів з ішемічною кардіоміопатією. Розроблена концепція оцінки критеріїв якості соматичних стовбурових клітин дозволить підвищити безпеку та ефективність клітинної терапії при пошкодженнях різних типів тканин та органів.. The outcome of the dissertation work is the resolution of a crucial scientific and practical issue: comprehending the pathogenetic mechanisms underpinning the realization of regenerative potential of somatic stem cells derived from diverse origins, considering their criteria for their quality and efficiency of application. The fundamental mechanisms underlying the realization of regenerative potential of stem cells of proper quality include their targeted migration to the site of injury, differentiation to substitute lost structural components, immunomodulatory effects aimed at dampening local inflammation, proangiogenic effects for neovascularization and restoration of perfusion in ischemic zones, prevention of apoptosis, and suppression of fibrosis. Based on these findings, a comprehensive framework has been devised to augment the safety and efficacy of cell therapy in the context of various tissue and organ injuries. The dissertation presents the results of establishing quality criteria and evaluating the preclinical effectiveness of somatic stem cells in laboratory animal models of tissue injury. To accomplish this, technologies for isolating, cultivating, directing differentiation, and multiparametric immunophenotyping of multipotent mesenchymal stromal cells (MMSCs) from adipose tissue, placenta, tissue-specific endothelial cells, and cardiac progenitor cells were developed. The study found that adipose-derived MMSCs exhibit a greater proliferative potential and population growth rate in comparison to those derived from bone marrow. However, when modelling adipose-derived stem cell niche dysfunction through ovariectomy, an increase in the population doubling time and a decrease in the potential for colony formation were observed, alongside an enhancement of adipogenesis in MMSC cultures in vitro.Transplants of adipose-derived MMSCs, differentiated in the osteogenic direction in three-dimensional micromass cultures, facilitate the regeneration of damaged bone tissue by replacing lost bone structures. These transplants exhibit improved morphological indicators of tissue restoration compared to transplants without prior differentiation. In a mouse model of critical limb ischemia, hydrogel with carbomer 974P, engrafted with adipose-derived MMSCs, supported the survival of transplanted cells and significantly enhanced perfusion, as well as improved the morpho-functional state of the damaged muscle tissue.The regenerative potential of endothelial progenitor cells was demonstrated through the restoration of perfusion in ischemic limbs and the improvement of histological indicators in muscle tissue in a model of critical limb ischemia. The use of Matrigel matrix and fibronectin as growth substrates was observed to promote the proliferation of endothelial progenitor cells and enhance their expression of endothelial markers, thereby facilitating their further implementation for therapeutic effects.It has been established that the proliferative potential and contractile activity of cardiac-derived progenitor cells in vitro decrease with an increasing age of the myocardial tissue donor. However, tissue-specific myocardial stem cells obtained from the atrial appendage exhibit superior proliferative potential and demonstrate distinct morphological and immunophenotypic characteristics when compared to cell cultures isolated from the ventricles. The study determined that the formation of cardiospheres of appropriate quality, exhibiting contractile activity in vitro and expressing troponin I, VEGFR-2, and CD31, requires the presence of cardiotrophin as a growth factor, along with a sequential change of poly-D-lysine and fibronectin as growth substrates.In a model of ischemic cardiomyopathy in mice, it was demonstrated that transplanted human placental MMSCs successfully engrafted the myocardium and exerted morphological and functional regenerative effects. When experimental studies were translated into a pilot clinical trial, the safety and efficacy of intramyocardial transplantation of human placental stem cells during surgical revascularization in patients with ischemic cardiomyopathy was confirmed. This innovative approach resulted in the restoration of the heart's contractile function, a rapid and significant reduction in heart failure symptoms, and an overall improvement in the patients' quality of life.The practical significance of the obtained results lies in the introduction of the latest high-tech cell therapy approaches, whose safety and effectiveness have been confirmed through experimental studies, and their translation into clinical practice. This advancement is expected to enhance the quality of complex treatment for patients with various serious diseases.
Дод. точки доступу:
Vitalii Kyryk; Буковинський державний медичний університет
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