👤 L B Buravkova

Cell senescence leads to a number of changes in the properties of mesenchymal stromal cells (MSCs). In particular, the number of damaged structures is increased producing negative effect on intracellular processes. Elimination of the damaged molecules and organelles occurs via autophagy that can be important in the context of aging. Cultivation under low oxygen level can be used as an approach for enhancement of MSC therapeutic properties and "slowing down" cell senescence. The goal of this work was to study some morphological and functional characteristics and expression of autophagy-associated genes during replicative senescence of MSCs under different oxygen concentration. The study revealed changes in the regulation of autophagy at the transcriptional level. Upregulation of the expression of autophagosome membrane growth genes ATG9A and ULK1, of the autophagosome maturation genes CTSD, CLN3, GAA, and GABARAPL1, of the autophagy regulation genes TP53, TGFB1, BCL2L1, FADD, and HTT was shown. These changes were accompanied by downregulation of IGF1 and TGM2 expression. Increase of the lysosomal compartment volume was observed in the senescent MSCs that also indicated increase of their degradation activity. The number of lysosomes was decreased following prolonged cultivation under low oxygen concentration (5%). The replicative senescence of MSCs under conditions of different oxygen levels led to the similar modifications in the expression of the autophagy-associated genes. Show less

Mesenchymal stromal cells (MSCs) are a population of adult stem cells that modulate functional state of neighboring tissues. During cell aging, the biological activity of MSC changes, which may affect tissue homeostasis. It is known that reducing the oxygen level in vitro to physiological values typical to a particular cell niche leads to attenuation of some morphological and functional changes associated with aging. This work aimed to study gene expression in MSCs involved in response to physiological hypoxia using a replicative aging model under physiological (5%) and atmospheric (20%) oxygen in cultures. Our results show that significant reduction of proliferative activity of MSCs is observed after 20 passages (~50 cell generations). Regardless of the oxygen, in senescent cells PKM2, SERPINE1, and VEGFA were upregulated while ANKRD37, DDIT4, HIF1A, and TXNIP were downregulated. Also, ADORA2B, BNIPL, CCNG2, EGLN1, MAP3K1, MXI1, and P4HA1 were downregulated under hypoxia. The effect of oxygen was more pronounced at earlier passages both on the cellular and transcription levels. Irrespective of the passage, genes ANGPTL4, GYS1, PKM2, SERPINE1, and TP53 were downregulated under hypoxia. Also, decreased expression was observed for ADM, F10, HMOX1, P4HB, PFKL, SLC16A3 in earlier passages, and for HK2 - in later passages. Upregulation was only observed for ANKRD37, both at early and late cultures. Show less

The ability of mesenchymal stromal (stem) cells (MSCs) to be mobilised from their local depot towards sites of injury and to participate in tissue repair makes these cells promising candidates for cell therapy. Physiological O Show less