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 (Ca oscillations), that change, especially in frequency, after the differentiation of the MSCs. Ca 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 Ca oscillations by physical means can facilitate osteodifferentiation of MSCs. Understanding the relationships between Ca oscillations and MSCs proliferation or differentiation appears necessary in the attractive perspective of influencing cell fate by controlling Ca signaling.

Methods: Using fluorescence microscopy we evaluated the evolution of Ca oscillations throughout the adipogenic and osteogenic differentiation processes. Then, using electrical stimulation with microsecond pulsed electric fields (µsPEFs), we manipulated the frequency of Ca oscillations in MSCs and measured its consequences on cell growth.

Results: Although the evolution of the Ca 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 Ca 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 Ca oscillations and the progression of the cell cycle, through some Ca sensitive molecular factors, could explain the evolutions of the frequencies of Ca oscillations observed during proliferation and differentiation. We hypothesized that increasing the frequency of Ca oscillations would promote proliferation, while decreasing it would promote differentiation under differentiating conditions. Using electrical stimulation with µsPEFs, we manipulated the frequency of Ca oscillations in MSCs and its increase actually promoted cell proliferation.

Conclusions: Manipulating the frequency of Ca oscillations influences the cell fate of MSCs. We propose hypotheses on the actors that could link the Ca oscillation frequencies with proliferation and differentiation processes, based on data available in the literature.