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.