Monovalent ions and stress-induced senescence in human mesenchymal endometrial stem/stromal cells

Monovalent ions are involved in growth, proliferation, differentiation of cells as well as in their death. This work concerns the ion homeostasis during senescence induction in human mesenchymal endometrium stem/stromal cells (hMESCs): hMESCs subjected to oxidative stress (sublethal pulse of H₂O₂) enter the premature senescence accompanied by persistent DNA damage, irreversible cell cycle arrest, increased expression of the cell cycle inhibitors (p53, p21) cell hypertrophy, enhanced β-galactosidase activity. Using flame photometry to estimate K⁺, Na⁺ content and Rb⁺ (K⁺) fluxes we found that during the senescence development in stress-induced hMESCs, Na⁺/K⁺pump-mediated K⁺ fluxes are enhanced due to the increased Na⁺ content in senescent cells, while ouabain-resistant K⁺ fluxes remain unchanged. Senescence progression is accompanied by a peculiar decrease in the K⁺ content in cells from 800-900 to 500-600 µmol/g. Since cardiac glycosides are offered as selective agents for eliminating senescent cells, we investigated the effect of ouabain on ion homeostasis and viability of hMESCs and found that in both proliferating and senescent hMESCs, ouabain (1 nM-1 µM) inhibited pump-mediated K⁺ transport (ID₅₀ 5 × 10^-8 M), decreased cell K⁺/Na⁺ ratio to 0.1-0.2, however did not induce apoptosis. Comparison of the effect of ouabain on hMESCs with the literature data on the selective cytotoxic effect of cardiac glycosides on senescent or cancer cells suggests the ion pump blockade and intracellular K⁺ depletion should be synergized with target apoptotic signal to induce the cell death.