Department of Intracellular Signaling and Transport, Institute of Cytology, Russian Academy of Sciences, Tikhoretsky Ave. 4, St-Petersburg, Russia, 194064.
Sci Rep. 2022 Jul 1;12(1):11194. doi: 10.1038/s41598-022-15490-2.
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 HO) 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/Kpump-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 (ID 5 × 10 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.
单价离子参与细胞的生长、增殖和分化，以及细胞的死亡。本工作涉及人间充质子宫内膜基质/干细胞（hMESCs）衰老诱导过程中的离子动态平衡：经历氧化应激（HO 亚致死脉冲）的 hMESCs 进入过早衰老，伴随着持续的 DNA 损伤、不可逆的细胞周期停滞、细胞周期抑制剂（p53、p21）表达增加、细胞肥大、β-半乳糖苷酶活性增强。通过火焰光度法估计 K、Na 含量和 Rb（K）通量，我们发现，在应激诱导的 hMESCs 衰老过程中，Na/K 泵介导的 K 通量增加，这是由于衰老细胞中 Na 含量增加，而哇巴因抗性 K 通量保持不变。衰老进展伴随着细胞内 K 含量从 800-900 µmol/g 到 500-600 µmol/g 的特殊减少。由于心脏糖苷被用作选择性试剂来消除衰老细胞，我们研究了哇巴因对 hMESCs 离子动态平衡和活力的影响，发现哇巴因（1 nM-1 µM）抑制了增殖和衰老 hMESCs 中的泵介导的 K 转运（ID 5×10 M），将细胞 K/Na 比值降低至 0.1-0.2，但不诱导细胞凋亡。将哇巴因对 hMESCs 的影响与心脏糖苷对衰老或癌细胞的选择性细胞毒性作用的文献数据进行比较，表明离子泵阻断和细胞内 K 耗竭应与靶向凋亡信号协同作用，以诱导细胞死亡。
