Breaking down calcium timing in heterogenous cells populations.

Calcium controls a large number of cellular processes at different scales. Decades of studies have pointed out the importance of calcium signaling in regulating differentiation, apoptosis, mitosis and functions such as secretion, muscle contraction and memory. The space-time structure of calcium signaling is central to this complex regulation. In particular, cells within organisms behave as clocks beating their own biological time, although in several cases they can synchronize across long distances leading to an emergent space-time dynamics which is central for single cell and organ functioning. We use a mathematical model built on published experimental data of hepatic non-excitable cells, analyzing emerging calcium dynamics of cells clusters composed both of normally functioning cells and pathological aggregates. Calcium oscillations are investigated by varying the severity of dysfunction and size of pathological aggregate. We show how strong and localized heterogeneity in cellular properties can profoundly alter organized calcium dynamics leading to sub-populations of cells which create their own coordinated dynamical organization. Our simulations of Ca2+ signals reveal how cell behaviors differ and are related to intrinsic time signals. Such different cells clusters dynamically influence each other so that non-physiological although organized calcium patterns are generated. This new reorganization of calcium activity may possibly be a precursor of cancer initiation.