Monovalent Ions and Stress-Induced Senescence in Human Mesenchymal Endometrial Stem Cells

2021 ◽  
Author(s):  
Alla Shatrova ◽  
Natalja Pugovkina ◽  
Alisa Domnina ◽  
Nikolaj Nikolsky ◽  
Irina Marakhova
Keyword(s):  
Stem Cells ◽  
Cardiac Glycosides ◽  
Ion Homeostasis ◽  
Ion Pump ◽  
H2o2 Treatment ◽  
Cycle Arrest ◽  
Monovalent Ions ◽  
Selective Agents ◽  
K Transport ◽  
K Depletion

Abstract 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 cells (hMESC): hMESCs subjected to oxidative stress (pulse H2O2 treatment) enter the premature senescence accompanied by persistent DNA damage, irreversible cell cycle arrest, cell hypertrophy, lipofuscin accumulation, 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 µmol/g 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, 24-48 h) inhibited pump-mediated K+ transport (ID50 5x10-8 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.

scholarly journals The Transcriptional Activator Imp2p Maintains Ion Homeostasis in Saccharomyces cerevisiae

Genetics ◽  
1998 ◽  
Vol 149 (2) ◽  
pp. 893-901
Author(s):  
Jean-Yves Masson ◽  
Dindial Ramotar
Keyword(s):  
Ion Homeostasis ◽  
Transcriptional Activator ◽  
Salt Resistance ◽  
Yeast Cells ◽  
Ion Pump ◽  
Multicopy Suppressor ◽  
Cation Homeostasis ◽  
Monovalent Ions ◽  
P Type ◽  
Oxidative Agents

Abstract Yeast cells deficient in the transcriptional activator Imp2p are viable, but display marked hypersensitivity to a variety of oxidative agents. We now report that imp2 null mutants are also extremely sensitive to elevated levels of the monovalent ions, Na+ and Li+, as well as to the divalent ions Ca2+, Mn2+, Zn2+, and Cu2+, but not to Cd2+, Mg2+, Co2+, Ni2+, and Fe2+, as compared to the parent strain. We next searched for multicopy suppressor genes that would allow the imp2Δ mutant to grow under high salt conditions. Two genes that independently restored normal salt-resistance to the imp2Δ mutant, ENA1 and HAL3, were isolated. ENA1 encodes a P-type ion pump involved in monovalent ion efflux from the cell, while HAL3 encodes a protein required for activating the expression of Ena1p. Neither ENA1 nor HAL3 gene expression was positively regulated by Imp2p. Moreover, the imp2 ena1 double mutant was exquisitely sensitive to Na+/Li+ cations, as compared to either single mutant, implying that Imp2p mediates Na+/Li+ cation homeostasis independently of Ena1p.

scholarly journals PAWI-2 overcomes tumor stemness and drug resistance via cell cycle arrest in integrin β3-KRAS-dependent pancreatic cancer stem cells

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jiongjia Cheng ◽  
John R. Cashman
Keyword(s):  
Cell Cycle ◽  
Pancreatic Cancer ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cell Cycle Arrest ◽  
Specific Inhibitor ◽  
Feedback Mechanism ◽  
Major Health Problem ◽  
Cycle Arrest ◽  
Drug Inhibition

Abstract Today, pancreatic cancer (PC) remains a major health problem in the US. The fact that cancer stem cells (CSCs) become enriched in humans following anti-cancer therapy implicates CSCs as key contributors to tumor dormancy, metastasis, and relapse in PC. A highly validated CSC model (FGβ3 cells) was used to test a novel compound (PAWI-2) to eradicate CSCs. Compared to parental bulk FG cells, PAWI-2 showed greater potency to inhibit cell viability and self-renewal capacity of FGβ3 cells. For FGβ3 cells, dysregulated integrin β3-KRAS signaling drives tumor progression. PAWI-2 inhibited β3-KRAS signaling independent of KRAS. This is clinically relevant. PAWI-2 targeted the downstream TBK1 phosphorylation cascade that was negatively regulated by optineurin phosphorylation via a feedback mechanism. This was confirmed by TBK1 genetic knockdown or co-treatment with TBK1-specific inhibitor (MRT67307). PAWI-2 also overcame erlotinib (an EGFR inhibitor) resistance in FGβ3 cells more potently than bortezomib. In the proposed working model, optineurin acts as a key regulator to link inhibition of KRAS signaling and cell cycle arrest (G2/M). The findings show PAWI-2 is a new approach to reverse tumor stemness that resensitizes CSC tumors to drug inhibition.

scholarly journals Cation-chloride cotransporters, Na/K pump, and channels in cell water and ions regulation: in silico and experimental studies of the U937 cells under stopping the pump and during RVD

2021 ◽  
Author(s):  
Alexey A Vereninov ◽  
Valentina Yurinskaya
Keyword(s):  
Plasma Membrane ◽  
Cell Membrane ◽  
Real Time ◽  
Intracellular Signaling ◽  
Ion Homeostasis ◽  
Regulatory Volume Decrease ◽  
Experimental Studies ◽  
U937 Cells ◽  
Ionic Homeostasis ◽  
Monovalent Ions

Cation-coupled chloride cotransporters play a key role in generating the Cl− electrochemical gradient on the cell membrane which is important for regulation of many cellular processes. However, the cooperation of transporters and channels of the plasma membrane in holding the ionic homeostasis of the whole cell remains poorly characterized because of the lack of a suitable tool for its computation. Our software successfully predicted in real-time changes in the ion homeostasis of U937 cells after stopping the Na/K pump, but so far considered the model with only NC cotransporter. Here the model with all main types of cotransporters is used in computation of the rearrangements of ionic homeostasis due to stopping the pump and associated with the regulatory volume decrease (RVD) of cells swollen in hypoosmolar medium. The parameters obtained for the real U937 cells are used. Successful prediction of changes in ion homeostasis in real-time after stopping the pump using the model with all major cotransporters indicates that the model is reliable. Using this model for analysis RVD showed that there is a "physical" RVD, associated with the time-dependent changes in electrochemical ion gradients, but not with alteration of channels and transporters of the plasma membrane that should be considered in studies of truly active regulatory processes mediated by the intracellular signaling network. The developed software can be useful for calculation of the balance of the partial unidirectional fluxes of monovalent ions across the cell membrane of various cells under various conditions.

scholarly journals Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

2021 ◽  
Author(s):  
Pavel I. Deryabin ◽  
Alla N. Shatrova ◽  
Aleksandra V. Borodkina
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Broad Spectrum ◽  
General Feature ◽  
Cardiac Glycosides ◽  
Human Mesenchymal Stem Cells ◽  
Apoptosis Resistance ◽  
The Core ◽  
Bioinformatic Approaches

AbstractTargeted elimination of senescent cells, senolysis, is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in ‘cardiac glycosides-sensitive’ A549 and ‘-insensitive’ hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis resistance in senescent hMSCs. Weakening “antiapoptotic defense” predisposes hMSCs to senolysis. We revealed that apoptosis resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant as compared to their proliferating counterparts. Graphic abstract

scholarly journals Muscle Stem Cells Undergo Extensive Clonal Drift during Tissue Growth via Meox1-Mediated Induction of G2 Cell-Cycle Arrest

2017 ◽  
Vol 21 (1) ◽  
pp. 107-119.e6 ◽  
Author(s):  
Phong Dang Nguyen ◽  
David Baruch Gurevich ◽  
Carmen Sonntag ◽  
Lucy Hersey ◽  
Sara Alaei ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Cell Cycle Arrest ◽  
Tissue Growth ◽  
Muscle Stem Cells ◽  
Cycle Arrest ◽  
G2 Cell Cycle Arrest

scholarly journals Functions of p53 in pluripotent stem cells

2019 ◽  
Vol 11 (1) ◽  
pp. 71-78 ◽  
Author(s):  
Xuemei Fu ◽  
Shouhai Wu ◽  
Bo Li ◽  
Yang Xu ◽  
Jingfeng Liu
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Mammalian Cells ◽  
Genomic Stability ◽  
Cell Types ◽  
The Body ◽  
Great Promise ◽  
Primary Role ◽  
Cycle Arrest ◽  
Clinical Potential

Abstract Pluripotent stem cells (PSCs) are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body, and thus hold great promise for regenerative medicine. To achieve their clinical potential, it is critical for PSCs to maintain genomic stability during the extended proliferation. The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells. In response to DNA damage or oncogenic stress, p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest, apoptosis, and senescence to prevent the passage of genetic mutations to the daughter cells. p53 is also required to maintain the genomic stability of PSCs. However, in response to the genotoxic stresses, a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency, providing mechanisms to maintain the genomic stability of the self-renewing PSCs. In addition, the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress. In summary, the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

Sign in / Sign up

Export Citation Format

Share Document