Assessment of the effect of hypoxia 1-induced factor on the immunomodulatory properties of human mesenchymal stromal cells.

Project goals. Mesenchymal stromal cells (MSCs) have the ability to influence the activity of various types of immune cells and are currently being tested as a therapeutic agent in numerous clinical trials. For several years, attention has been drawn to the fact that hypoxic conditions significantly affect the immune response profile. It is also known that the state of reduced oxygen availability in the environment stimulates in MSC the activation of HIF-1, a transcription factor that influences the expression of several hundred genes. However, the importance of HIF-1 activation for the interaction between immune cells and MSCs has not yet been thoroughly investigated. The aim of this project is to determine the influence of HIF-1 on the immunomodulatory properties of MSC cells. The main research hypotheses of this project are the following: 1) HIF-1 activation significantly influences the immunomodulatory effect of MSC; 2) by modifying the activity of HIF-1 in MSCs using chemical methods or cellular engineering, and also in combination with inhibitors of selected cytokines (e.g. IL-6), the therapeutic potential of MSCs in terms of immunomodulation can be influenced; 3) the effect of HIF-1 activation on the immunomodulatory properties of MSCs varies depending on the origin of the cells. Expected results. The immunomodulatory properties of MSCs raise great hopes. However, the results of clinical trials to date are not as promising as the results of in vitro studies. Therefore, it is crucial to conduct further basic research using modern analytical methods that will deepen the current knowledge about the potential of MSC. The determination of the impact of HIF-1 activation in MSCs on their immunomodulatory properties is intended to allow for a better understanding of the mechanisms of the physiological and therapeutic effects of MSCs.We expect that determining the effect of hypoxia on the interactions between MSCs and inflammatory cells will provide a better understanding of the differences in the effectiveness of using MSCs in various disease states. Finally, the obtained results can form the basis for the definition of new strategies for enhancing the immunomodulatory potential of MSCs. Units involved: The project manager is Prof. Leszek Pączek. The research will be performed mainly in the cell culture laboratory of the Department of Immunology, Transplantology and Internal Diseases of the Medical University of Warsaw under the direct supervision of Dr Anna Burdzińska. The second unit involved in the implementation of the project will be the Department of Clinical Immunology of the Medical University of Warsaw under the supervision of dr hab. Radosław Zagożdżon. Human cells will be obtained from the bone marrow (cooperation with the Department of Orthopedics and Traumatology of the Motor System of the Medical University of Warsaw), and also from umbilical cords (cooperation with the Department of Obstetrics and Gynecology of the Medical University of Warsaw).