Calcium oscillations in Mesenchymal Stem Cells, a control on cell cycle progression to influence cell fate towards proliferation or differentiation?

Abstract Background Mesenchymal stem cells (MSCs) have been shown to exhibit Ca2+ oscillations under regular culture conditions. Ca2+ oscillations are known to encode important information in their frequencies as well as in their amplitudes, and ultimately to control many cellular processes such as proliferation and differentiation. These Ca2+ oscillations are modified in cells differentiated from MSCs, especially in their frequencies. Understanding the regulation of the Ca2+ oscillations in MSCs, either during proliferation or differentiation, is a necessary step in the attractive perspective of controlling Ca2+ signaling to influence cell fate. Previous studies have shown that the application of a low amplitude direct current electric field, which decreased the frequency of Ca2+ oscillations in MSCs undergoing osteogenic differentiation, had an impact on the differentiation process.Methods Using fluorescent microscopy we evaluated the evolution of Ca2+ oscillations throughout the adipogenic and osteogenic differentiation processes. Then, using electrical stimulation with microsecond pulsed electric fields (µsPEFs), we manipulated the frequency of Ca2+ oscillations in MSCs and measured its consequences on cell growth.Results Although the evolution of the Ca2+ oscillation frequencies at the beginning of the differentiation processes was different between the adipogenic and osteogenic differentiations, we observed common features in the terminal stages of differentiation. The common features included a progressive decrease in the Ca2+ oscillation frequencies, before their complete arrest as the differentiations were arriving to their term. A relationship between the frequency of Ca2+ oscillations and the progression of the cell cycle, more precisely the G1 phase, could explain the frequencies of Ca2+ oscillations observed during proliferation and along the differentiations. We hypothesized that increasing the frequency of Ca2+ oscillations would promote proliferation, while decreasing it would promote differentiation under differentiating conditions. Using electrical stimulation with µsPEFs, we manipulated the frequency of Ca2+ oscillations in MSCs and their increase promoted cell proliferation.Conclusions The cell fate of MSCs, in particular cell growth, can be controlled by manipulating the frequency of Ca2+ oscillations. We propose hypotheses on the actors that could regulate the evolution of the Ca2+ oscillation frequency along the differentiation processes, based on data available in the literature.