Spontaneous Calcium Oscillations Regulate Human Cardiac Progenitor Cell Growth

Rationale: The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. Objective: Ca(2+) promotes cell growth raising the possibility that changes in intracellular Ca(2+) initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. Methods and Results: Ca(2+) oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca(2+). These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca(2+) oscillations in hCPCs were regulated by the release of Ca(2+) from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca(2+) by the sarco-/endoplasmic reticulum Ca(2+) pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na(+)-Ca(2+) exchanger, store-operated Ca(2+) channels and plasma membrane Ca(2+) pump were present and functional in hCPCs, they had no direct effects on Ca(2+) oscillations. Conversely, Ca(2+) oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca(2+) oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca(2+) oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. Conclusion: IP3R-mediated Ca(2+) mobilization control hCPC growth and their regenerative potential. (Circ Res. 2009; 105: 764-774.)