1. Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.
- Author
-
Ferreira-Martins J, Rondon-Clavo C, Tugal D, Korn JA, Rizzi R, Padin-Iruegas ME, Ottolenghi S, De Angelis A, Urbanek K, Ide-Iwata N, D'Amario D, Hosoda T, Leri A, Kajstura J, Anversa P, and Rota M
- Subjects
- Adenosine Triphosphate pharmacology, Adult, Animals, Endoplasmic Reticulum metabolism, Gene Expression Regulation drug effects, Gene Expression Regulation physiology, Histamine pharmacology, Humans, Inositol 1,4,5-Trisphosphate Receptors metabolism, Mice, Mice, Transgenic, Myocardium cytology, Myocytes, Cardiac cytology, Proto-Oncogene Proteins c-kit metabolism, Receptors, Histamine metabolism, Receptors, Purinergic metabolism, Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism, Stem Cells cytology, Biological Clocks physiology, Calcium metabolism, Myocardium metabolism, Myocytes, Cardiac metabolism, Stem Cells metabolism
- Abstract
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.
- Published
- 2009
- Full Text
- View/download PDF