Differential Mechanisms of Myocardial Conduction Slowing by Adipose Tissue-Derived Stromal Cells Derived from Different Species

Abstract

Stem cell therapy is a promising therapeutic option to treat patients after myocardial infarction. However, the intramyocardial administration of large amounts of stem cells might generate a proarrhythmic substrate. Proarrhythmic effects can be explained by electrotonic and/or paracrine mechanisms. The narrow therapeutic time window for cell therapy and the presence of comorbidities limit the application of autologous cell therapy. The use of allogeneic or xenogeneic stem cells is a potential alternative to autologous cells, but differences in the proarrhythmic effects of adipose‐derived stromal cells (ADSCs) across species are unknown. Using microelectrode arrays and microelectrode recordings, we obtained local unipolar electrograms and action potentials from monolayers of neonatal rat ventricular myocytes (NRVMs) that were cocultured with rat, human, or pig ADSCs (rADSCs, hADSCs, pADSCs, respectively). Monolayers of NRVMs were cultured in the respective conditioned medium to investigate paracrine effects. We observed significant conduction slowing in all cardiomyocyte cultures containing ADSCs, independent of species used (p < .01). All cocultures were depolarized compared with controls (p < .01). Only conditioned medium taken from cocultures with pADSCs and applied to NRVM monolayers demonstrated similar electrophysiological changes as the corresponding cocultures. We have shown that independent of species used, ADSCs cause conduction slowing in monolayers of NRVMs. In addition, pADSCs exert conduction slowing mainly by a paracrine effect, whereas the influence on conduction by hADSCs and rADSCs is preferentially by electrotonic interaction. Stem Cells Translational Medicine 2017;6:22–30

Recombinant human collagen-based microspheres mitigate cardiac conduction slowing induced by adipose tissue-derived stromal cells

“…We demonstrated earlier that ASC from three species cause heterogeneous conduction slowing. Human and rat ASC exert a direct-electrotonic-coupling effect, those from porcine exert paracrine effects[10]. In the current study, we show that application of bare microspheres has no effect on conduction properties of NRVM monolayers (Fig 4).…”

“…However, we demonstrated before[10] and in the current study, that physical contact between porcine ASC and cardiomyocytes is not required for heterogeneous conduction slowing. When bare pASC or factors secreted from pASC are cultured with NRVM heterogeneous conduction slowing is observed in monolayers of NRVM.…”

“…Conditioned medium obtained from pASC cultures induced conduction slowing and increased conduction heterogeneity (Fig 6, 2 nd bar), as demonstrated before[10]. We tested whether the mitigated effect of the microspheres (Fig 5) was related to primary paracrine effects derived from the porcine stem cells (pASC).…”

“…From the previous study we observed that ASC depolarized the co-cultures[10]. Here, we recorded action potentials from monolayers of NRVM co-cultured with pASC loaded microspheres, monolayers of NRVM cultured in conditioned medium and control monolayers.…”

“…Therefore, 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]. …”