Angiotensin model as a new approach to study of mesenchymal stem cell senescence

Background. Aging contributes to pathological changes in tissues aggravating the course of cardiovascular, nervous and other diseases. Senescence of mesenchymal stem cells (MSCs) leading to release of proinflammatory factors contributes to fibrosis. Persistent pathologically high concentration of angiotensin II (ANG) causes aging of various cells, but its effect on senescence of MSCs has not yet been studied. Objective. To develop a model of cellular senescence induced by long-term exposure of MSC culture to angiotensin and to evaluate the possibilities of its pharmacological regulation. Results. Long-term exposure to ANG reduces MSC proliferation, enhances expression of senescence-associated beta-galactosidase and cell cycle inhibitors, proteins p21 and p53, increases secretion of some factors stimulating migration of inflammatory and immune cells, as well as VEGF. Increased transcription of matrix metalloproteinases MMP1, MMP3 and MMP9 was also detected without changes in transcription of inhibitors (TIMP2 and TIMP3). The angiotensin receptor antagonist telmisartan does not induce expression of senescence markers and does not significantly affect angiotensin-induced secretion. Melatonin with antioxidant effect does not potentiate expression of senescence markers, and in some cases suppresses secretion of angiotensin-inducible factors. At the same time, melatonin is able to enhance secretion of some factors in MSCs without being a pro-senescence factor. Conclusion. Long-term exposure of MSC culture to angiotensin induces appearance of senescence markers, as well as formation of specific senescence-associated secretory phenotype. Potential effects of telmisartan and melatonin on angiotensin-inducible senescence in MSCs allow us to consider these drugs as potential senescence modulators.