Abstract
BackgroundStem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may also increase the risk of arrhythmias by providing an arrhythmogenic substrate. We previously showed that porcine adipose tissue-derived-stromal cells (pASC) induce conduction slowing through paracrine actions, whereas rat ASC (rASC) and human ASC (hASC) induce conduction slowing by direct coupling. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling.AimTo investigate the modulation of ASC-loaded recombinant human collagen-based microspheres, on the electrophysiological behavior of neonatal rat ventricular myocytes (NRVM).MethodUnipolar extracellular electrograms, derived from microelectrode arrays (8x8 electrodes) containing NRVM, co-cultured with ASC or ASC loaded microspheres, were used to determine conduction velocity (CV) and conduction heterogeneity. Conditioned medium (Cme) of (co)cultures was used to assess paracrine mechanisms.ResultsMicrospheres did not affect CV in control (NRVM) monolayers. In co-cultures of NRVM and rASC, hASC or pASC, CV was lower than in controls (14.4±1.0, 13.0±0.6 and 9.0± 1.0 vs. 19.5±0.5 cm/s respectively, p<0.001). Microspheres loaded with either rASC or hASC still induced conduction slowing compared to controls (13.5±0.4 and 12.6±0.5 cm/s respectively, p<0.001). However, pASC loaded microspheres increased CV of NRVM compared to pASC and NRMV co-cultures (16.3±1.3 cm/s, p< 0.001) and did not differ from controls (p = NS). Cme of pASC reduced CV in control monolayers of NRVM (10.3±1.1 cm/s, p<0.001), similar to Cme derived from pASC-loaded microspheres (11.1±1.7 cm/s, p = 1.0). The presence of microspheres in monolayers of NRVM abolished the CV slowing influence of Cme pASC (15.9±1.0 cm/s, p = NS vs. control).ConclusionThe application of recombinant human collagen-based microspheres mitigates indirect paracrine conduction slowing through interference with a secondary autocrine myocardial factor.
Highlights
Stem cell-based therapy is an experimental clinical therapeutic option to improve cardiac function and remodeling in post-myocardial infarction patients[1,2,3,4]
We have recently shown that adipose tissue-derived stromal cells (ASC) cause heterogeneous conduction slowing in cultured neonatal rat ventricular myocytes (NRVM) monolayers
Paracrine modulation and intercellular coupling between the ASC and NRVM contribute to the formation of a potentially pro-arrhythmic substrate
Summary
Stem cell-based therapy is an experimental clinical therapeutic option to improve cardiac function and remodeling in post-myocardial infarction patients[1,2,3,4]. Direct—electrotonic- coupling between stem cells and cardiac myocytes will exert electrophysiological effects that alter the electrophysiology that can result in conduction slowing [7, 8, 10] and reentrant arrhythmias [13, 14]. There is consensus that the hemodynamic benefit of stem cells on cardiac function seen in several pre-clinical post-(acute) myocardial infarction studies is mediated by paracrine signaling. Stem cell therapy to improve cardiac function after myocardial infarction is hampered by poor cell retention, while it may increase the risk of arrhythmias by providing an arrhythmogenic substrate. We postulate that biomaterial microspheres mitigate the conduction slowing influence of pASC by interacting with paracrine signaling
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