Spontaneous calcium oscillations regulate human cardiac progenitor cell growth

Circ Res. 2009 Oct 9;105(8):764-74. doi: 10.1161/CIRCRESAHA.109.206698. Epub 2009 Sep 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Adult
  • Animals
  • Biological Clocks / physiology*
  • Calcium / metabolism*
  • 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
  • Myocardium / metabolism*
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism*
  • Proto-Oncogene Proteins c-kit / metabolism
  • Receptors, Histamine / metabolism
  • Receptors, Purinergic / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism*

Substances

  • Inositol 1,4,5-Trisphosphate Receptors
  • Receptors, Histamine
  • Receptors, Purinergic
  • Histamine
  • Adenosine Triphosphate
  • Proto-Oncogene Proteins c-kit
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium