| Autor: |
Smit NW; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.; Netherlands Heart Institute, Utrecht, Netherlands., Cócera Ortega L; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Végh AMD; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands., Meijborg VMF; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.; Netherlands Heart Institute, Utrecht, Netherlands., Smits AM; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands., Klerk M; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Tijsen AJM; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Tan HL; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Goumans MHT; Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, Netherlands., Boink GJJ; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands., Coronel R; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands.; IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, Bordeaux, France. |
| Abstrakt: |
Background: Cardiomyocyte progenitor cells (CMPCs) are a promising cell source for regenerative cell therapy to improve cardiac function after myocardial infarction. However, it is unknown whether undifferentiated CMPCs have arrhythmogenic risks. We investigate whether undifferentiated, regionally applied, human fetal CMPCs form a pro-arrhythmic substrate in co-culture with neonatal rat ventricular myocytes (NRVMs). Method: Unipolar extracellular electrograms, derived from micro-electrode arrays (8 × 8 electrodes) containing monolayers of NRVMs (control), or co-cultures of NRVMs and locally seeded CMPCs were used to determine conduction velocity and the incidence of tachy-arrhythmias. Micro-electrodes were used to record action potentials. Conditioned medium (Cme) of CMPCs was used to distinguish between coupling or paracrine effects. Results: Co-cultures demonstrated conduction slowing (5.6 ± 0.3 cm/s, n = 50) compared to control monolayers (13.4 ± 0.4 cm/s, n = 26) and monolayers subjected to Cme (13.7 ± 0.6 cm/s, n = 11, all p < 0.001). Furthermore, co-cultures had a more depolarized resting membrane than control monolayers (-47.3 ± 17.4 vs. -64.8 ± 7.7 mV, p < 0.001) and monolayers subjected to Cme (-64.4 ± 8.1 mV, p < 0.001). Upstroke velocity was significantly decreased in co-cultures and action potential duration was prolonged. The CMPC region was characterized by local ST-elevation in the recorded electrograms. The spontaneous rhythm was faster and tachy-arrhythmias occurred more often in co-cultured monolayers than in control monolayers (42.0 vs. 5.4%, p < 0.001). Conclusion: CMPCs form a pro-arrhythmic substrate when co-cultured with neonatal cardiomyocytes. Electrical coupling between both cell types leads to current flow between a, slowly conducting, depolarized and the normal region leading to local ST-elevations and the occurrence of tachy-arrhythmias originating from the non-depolarized zone. |
