Calcium oscillations in mesenchymal stem cells, a control on cell cycle progression to influence cell fate towards...

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 Ca^2 + oscillations by physical means can facilitate osteodifferentiation of MSCs. Understanding the relationships between Ca^2 + oscillations and MSCs proliferation or differentiation appears necessary in the attractive perspective of influencing cell fate by controlling Ca^2 + signaling.

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.

Although the evolution of the Ca^2 + 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^2 + 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 Ca^2 + 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.

Manipulating the frequency of Ca^2 + oscillations influences the cell fate of MSCs. We propose hypotheses on the actors that could link the Ca^2 + oscillation frequencies with proliferation and differentiation processes, based on data available in the literature.