Abstract
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.
Highlights
Regenerative cell therapies are being developed for patients suffering from heart failure and acute or chronic myocardial infarction (Laflamme and Murry, 2005)
action potential (AP) recorded in control monolayers and monolayers of neonatal rat ventricular myocytes (NRVMs) cultured in Conditioned medium (Cme) Cardiomyocyte progenitor cells (CMPCs) demonstrated ventricular-type APs (Figure 1A, left and right panel)
resting membrane potential (RMP) was normally distributed in all three group (Shapiro-Wilks test: NRVM: 0.50, NRVM+CMPC: 0.08 and Cme CMPC: 0.57)
Summary
Regenerative cell therapies are being developed for patients suffering from heart failure and acute or chronic myocardial infarction (Laflamme and Murry, 2005). If coupling between stem cells and cardiomyocytes occurs, the electrotonic interaction may cause cardiomyocytes to become depolarized (Askar et al, 2013; Ten Sande et al, 2016) and less excitable If this occurs in a spatially heterogeneous manner (e.g., cells applied via injections), this causes regional heterogeneous conduction slowing that can lead to unidirectional block and re-entrant arrhythmias (Lammers et al, 1990). Cardiomyocyte progenitor cells (CMPCs) are a promising cell source for regenerative cell therapy to improve cardiac function after myocardial infarction. It is unknown whether undifferentiated CMPCs have arrhythmogenic risks. Regionally applied, human fetal CMPCs form a pro-arrhythmic substrate in co-culture with neonatal rat ventricular myocytes (NRVMs)
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