Increasing cytosolic Ca2+ levels restore cell proliferation and stem cell potency in aged MSCs

Abstract

Aging is an inescapable complex physiological but extendable process, and all cells, including stem cells, are altered over time. Diverse mechanism(s) could modulate stem cell number, their proliferation rate, and promote tissue repair during aging that leads to longevity. However, the factors that could restore aging stem cell potency and would lead to healthy aging are not fully identified. Here we show that maintaining cytosolic Ca 2+ levels was essential for modulating stem cells function in aged mesenchymal stem cells (MSCs). Increasing external Ca 2+ induced spindle shape stem cell morphology and maintained stem cell surface marker expression in aged bone marrow-derived MSCs. Similarly, stem cell survival and proliferation of aged MSCs was dependent on cytosolic Ca 2+ levels. Importantly, Ca 2+ entry potentiated cell cycle progression, and stem cell potential was increased in cells incubated with higher external Ca 2+ . Moreover, blocking Ca 2+ entry using SKF 96365, decreased stem cell survival and its proliferation but, treatment with 2-APB did not significantly affected cell proliferation, rather only modulated cell viability. Evaluation of Ca 2+ entry channels, showed that TRPC1/Orai1/Orai3 and their regulator STIM1 was essential for MSCs proliferation/viability as gene silencing of Orai1/Orai3/TRPC1/STIM1 significantly inhibited stem cell viability. Finally, MSCs isolated from aged mice that were subjected to higher Ca 2+ levels, were able to rescue age-induced loss of MSCs function. Together these results suggest that Ca 2+ entry is essential for preventing the loss of aged stem cell function and supplementing Ca 2+ not only restored their proliferative potential but, allowed them to develop into younger stem cell lineages that could be critical for regenerative medicine.

Piezoelectric hydrogel for treatment of periodontitis through bioenergetic activation

“…A sustained increase in [Ca 2+ ] i with elevated Δψ m was previously reported in hematopoietic stem cells upon stress hematopoiesis to initiate cell division [ 51 ]. An increase in [Ca 2+ ] i was also found to be capable of restoring the proliferative potential and rescuing age-induced loss of MSC function [ 52 ]. The positive feedback between [Ca 2+ ] i elevation and ATP production from mitochondria can satisfy the increased energetic demand in various cell behaviors [ 53 ].…”

Enhanced TRPC3 transcription through AT1R/PKA/CREB signaling contributes to mitochondrial dysfunction in renal tubular epithelial cells in D‐galactose‐induced accelerated aging mice

“…Therefore, dysregulated calcium homeostasis has been shown to function in aging-associated disorders. Previously, increased cytosolic Ca 2+ levels were observed in aging MSCs (Ahamad et al, 2021), and were correlated with age-related diseases (Madreiter-Sokolowski et al, 2020). Moreover, targeting mitochondrial calcium homeostasis is a therapeutic strategy to improve aging-associated diseases (Gao et al, 2020;Lee et al, 2021).…”

“…Among the various regulatory functions of mitochondria, calcium homeostasis is considered important in various pathological conditions. Dysregulated calcium status exists in aged mesenchymal stem cells and aging rat aorta (Ahamad et al, 2021;Erac et al, 2010), while we have previously shown that modulation of mitochondrial calcium overload ameliorates age-associated disorders (Gao et al, 2020). Moreover, calcium, ROS, and mitochondria comprise a close triangle that modulate not only cell function and cell fate, but also functions involved in aging and age-associated diseases (Madreiter-Sokolowski et al, 2020).…”

Store-Operated Ca2+ Entry as a Putative Target of Flecainide for the Treatment of Arrhythmogenic Cardiomyopathy

“…Therefore, we still do not know whether they support SOCE in BM-hMSCs. Nevertheless, genetic silencing of STIM1, Orai1, and/or Orai3 reduced SOCE in mouse BM-derived MSCs (BM-mMSCs) [ 79 , 80 , 81 ] and in human dental pulp-derived MSCs (DP-hMSCs) [ 82 ].…”