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(Circulation Research. 2009;105:764.)
© 2009 American Heart Association, Inc.

Cellular Biology

Spontaneous Calcium Oscillations Regulate Human Cardiac Progenitor Cell Growth

João Ferreira-Martins^*, Carlos Rondon-Clavo^*, Derin Tugal, Justin A. Korn, Roberto Rizzi, Maria Elena Padin-Iruegas, Sergio Ottolenghi, Antonella De Angelis, Konrad Urbanek, Noriko Ide-Iwata, Domenico D'Amario, Toru Hosoda, Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota

From the Departments of Anesthesia and Medicine and Cardiovascular Division (J.F.-M., C.R.-C., D.T., J.A.K., R.R., M.E.P.-I., A.D.A., K.U., N.I.-I., D.D., T.H., A.L., J.K., P.A., M.R.), Brigham & Women’s Hospital, Harvard Medical School, Boston, Mass; and Department of Biotechnology and Bioscience (S.O.), University of Milano-Bicocca, Milan, Italy.

Correspondence to Marcello Rota, PhD, Departments of Anesthesia and Medicine, and Cardiovascular Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA 02115. E-mail mrota{at}zeus.bwh.harvard.edu

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.

Key Words: human cardiac progenitor cells • calcium oscillations • cell growth