Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.
BACKGROUND
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.


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.


CONCLUSIONS
IP3R-mediated Ca2+ mobilization control hCPC growth and their regenerative potential.
Ferreira-Martins
João
J
Department of Anesthesia and Cardiovascular Division, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Rondon-Clavo
Carlos
C
Tugal
Derin
D
Korn
Justin A
JA
Rizzi
Roberto
R
Padin-Iruegas
Maria Elena
ME
Ottolenghi
Sergio
S
De Angelis
Antonella
A
Urbanek
Konrad
K
Ide-Iwata
Noriko
N
D'Amario
Domenico
D
Hosoda
Toru
T
Leri
Annarosa
A
Kajstura
Jan
J
Anversa
Piero
P
Rota
Marcello
M
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D011968:Receptors, Histamine; D011983:Receptors, Purinergic; D006632:Histamine; D000255:Adenosine Triphosphate; D019009:Proto-Oncogene Proteins c-kit; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium