Background The safety of cardiac cell therapy with human mesenchymal stem cell (hMSC) has not been clearly established. We investigated whether hMSC transplantation with or without epicardial pacing (P) changes the distribution of cardiac autonomic nerve and gap junction, resulting in arrhythmia in canine heart.
Methods and Results We monitored the cardiac rhythm for 4 weeks after hMSC transplantation (1x107, epicardial injection) or P in 18 dogs in vivo (7 hMSC+P, 6 hMSC, and 5 Sham), and evaluated their sympathetic innervation using nerve growth factor (NGF)-ß and tyrosine hydroxylase (TH)), angiogenesis using vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF), and gap junction expression with Cx43. Results: 1. Sudden death caused by
ventricular fibrillation occurred in hMSC+P (n=2, 28.5%) and hMSC (n=1, 16.6%). 2. hMSC hearts expressed higher NGF-ß mRNA (56.0±66.8 fold, p<0.01) with TH+ sympathetic nerves (0.51±0.40% vs. 0.15±0.13%, p<0.05), as well as higher VEGF mRNA (7.09±6.94 fold, p<0.001) with vWF+ vessels (0.69±0.49% vs. 0.16±0.18%, p<0.001) than the Sham group. 3. In contrast, hMSC hearts expressed lower Cx43 mRNA (0.59±0.29 fold, p<0.0001) with Cx43+ gap junctions (1.64±0.79% vs. 2.12±1.07%, p<0.001) than the Sham. 4. hMSC+P hearts expressed higher Cx43 mRNA (2.04±1.39 fold, p<0.02) than the Sham, and higher Cx43+ gap junctions (3.02±1.54%)compared with hMSC (1.64±0.78%, p<0.001) or Sham (2.47±1.16%, p<0.001), but did not change the expressions of NGF and VEGF compared with Sham. Neither in vitro hMSC+P changed NGF-ß and VEGF, and rather reduced Cx43 (0.76±0.11 fold, p<0.02).
Conclusion hMSC increased NGF-ß induced cardiac sympathetic hyperinnervation and VEGF induced angiogenesis, but reduced gap junction expression after transplanted in the canine heart, which causes ventricular arrhythmia. In contrast, electrical pacing increased gap junction by paracrine action.
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