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: Ca²⁺ promotes cell growth raising the possibility that changes in intracellular Ca²⁺ initiate division of c-kit–positive human cardiac progenitor cells (hCPCs) and determine their fate.

Methods and Results: Ca²⁺ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca²⁺. 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. Ca²⁺ oscillations in hCPCs were regulated by the release of Ca²⁺ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca²⁺ by the sarco-/endoplasmic reticulum Ca²⁺ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na⁺-Ca²⁺ exchanger, store-operated Ca²⁺ channels and plasma membrane Ca²⁺ pump were present and functional in hCPCs, they had no direct effects on Ca²⁺ oscillations. Conversely, Ca²⁺ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca²⁺ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca²⁺ 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 Ca²⁺ mobilization control hCPC growth and their regenerative potential.