Human mesenchymal stem cell transplantation induces sympathetic nerve sprouting and reduces the gap junction with potential proarrhythmias in dogs

Background and Objectives: Although human mesenchymal stem cell (hMSC) transplantation has been known to improve ventricular function, the potential proarrhythmic effects have not yet been studied. Materials and Methods: We monitored the heart rhythm of 6 dogs for 4 weeks after transplantation of hMSC (1 × 10⁷, epicardial injection) (hMSC group) and in 5 Sham dogs after the injection of the vehicle alone. Cardiac sympathetic nerve sprouting {nerve growth factor (NGF)- β; tyrosine hydroxylase (TH)} and gap junction expression {connexin (Cx) 43) were evaluated in 10 dogs (5 hMSC and 5 Sham) that survived longer than 4 weeks. Results: The hMSC group expressed higher levels of NGF- β messenger ribonucleic acid (mRNA) (56.0 ± 66.8 fold; p<0.01) with TH+ sympathetic nerves (0.51 ± 0.40 vs. 0.15 ± 0.13% area; p<0.03) than the Sham control. In contrast, the hMSC group expressed lower levels of Cx43 mRNA (0,59 ± 0.29 fold, p<0.001) and Cx43+ (1.64 ± 1.79 vs. 2.12 ± 1.07% area, p<0.001) than the Sham control. The incidences of ventricular fibrillation were 33.3% and 0% in the hMSC group and Sham control, respectively. One of the dogs with ventricular fibrillation (VF) in the hMSC group died suddenly. Conclusion: hMSC transplantation may be proarrhythmic since NGF- β expression increased with cardiac sympathetic hyperinnervation and the expression of Cx43 and the gap junction decreased.