Calcium oscillations in mesenchymal stem cells, a control on cell cycle progression to influence cell fate towards proliferation or differentiation?

Background: Under regular culture conditions, mesenchymal stem cells (MSCs) exhibit cytosolic calcium concentration oscillations (Ca2+ oscillations), that change, especially in frequency, after the differentiation of the MSCs. Ca2+ oscillations are known to encode important information in frequency and amplitude, ultimately controlling many cellular processes such as proliferation and differentiation. Previous studies evidenced that decreasing the frequency of Ca2 + oscillations by physical means can facilitate osteodifferentiation of MSCs. Understanding the relationships between Ca2 + oscillations and MSCs proliferation or differentiation appears necessary in the attractive perspective of influencing cell fate by controlling Ca2 + signaling. Methods: Using fluorescence 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 differed between the adipogenic and osteogenic differentiation pathways in early stages of differentiation, we observed common features in the late stages: a progressive decrease in the Ca2 + oscillations frequencies, before their complete arrest as the differentiations reached their term. It has been reported that most cells undergoing differentiation experience a concomitant commitment to terminal differentiation and cell cycle exit, and prior to this, lengthened G1 phases, where the molecular competition between mitogenic and differentiating signals occurs. A relationship between the frequency of Ca2+ oscillations and the progression of the cell cycle, through some Ca2 + sensitive molecular factors, could explain the evolutions of the frequencies of Ca2+ oscillations observed during proliferation and differentiation. 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 its increase actually promoted cell proliferation. Conclusions: Manipulating the frequency of Ca2 + oscillations influences the cell fate of MSCs. We propose hypotheses on the actors that could link the Ca2 + oscillation frequencies with proliferation and differentiation processes, based on data available in the literature.