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Generation of Murine Cardiac Pacemaker Cell Aggregates Based on ES-Cell-Programming in Combination with Myh6-Promoter-Selection
Published on: February 17, 2015
Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit.
V Valiunas1, G Kanaporis, L Valiuniene
1Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794-8661, USA.
The Journal of Physiology
|September 9, 2009
Summary
Engineered non-myocytes expressing HCN2, coupled to cardiac myocytes via gap junctions, can create a biological pacemaker. This cell pair generates sustained electrical activity, paving the way for in vivo pacemaker development.
Area of Science:
- Biotechnology
- Cardiovascular Research
- Cellular Electrophysiology
Background:
- Biological pacemakers offer an alternative to electronic devices for treating cardiac arrhythmias.
- Understanding cell-cell communication is crucial for developing functional, engineered cardiac tissues.
Purpose of the Study:
- To investigate if coupling a ventricular myocyte with a non-myocyte cell expressing HCN2 can create a self-sustaining pacemaker unit.
- To determine the role of gap junction coupling and HCN2 currents in generating spontaneous electrical activity.
Main Methods:
- Co-culture of ventricular myocytes with non-myocyte cell lines (HEK293, HeLa, mesenchymal stem cells) engineered to express the HCN2 gene.
- Measurement of cell-cell coupling using electrophysiological techniques and assessment of induced currents.
- Pharmacological manipulation using gap junction blockers (carbenoxolone) and HCN2 channel blockers (THA) to assess their effects on pacing.
Main Results:
- Successful electrical coupling was established between myocytes and HCN2-expressing non-myocytes, with coupling strength increasing over time.
- HCN2 currents were successfully transferred from non-myocytes to myocytes, inducing spontaneous action potentials at frequencies of 0.6-1.7 Hz.
- Pharmacological blockade of gap junctions or HCN2 channels abolished spontaneous activity, which was restored upon washout, confirming the mechanism.
Conclusions:
- A two-cell syncytium of a myocyte and an HCN2-expressing non-myocyte can function as a biological pacemaker.
- Gap junction communication is essential for transferring the pacemaking current from the engineered cell to the myocyte.
- This study provides a foundation for developing cell-based biological pacemakers for therapeutic applications.
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