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 promotes cell growth raising the possibility that changes in intracellular Ca initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. METHODS AND RESULTS:: Ca oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca. 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 oscillations in hCPCs were regulated by the release of Ca from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca by the sarco-/endoplasmic reticulum Ca pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na-Ca exchanger, store-operated Ca channels and plasma membrane Ca pump were present and functional in hCPCs, they had no direct effects on Ca oscillations. Conversely, Ca oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca 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 mobilization control hCPC growth and their regenerative potential.