Cardiac cell therapy with mesenchymal stem cell induces cardiac nerve sprouting, angiogenesis, and reduced connexin43-positive gap junctions, but concomitant electrical pacing increases connexin43-positive gap junctions in canine heart

Abstract

Background: Although electrical pacing is of great utility in many cardiovascular diseases, its effects on the combined cardiac cell therapy have not been established. We hypothesised that mesenchymal stem cell transplantation changes cardiac sympathetic nerve and gap junction, and concomitant pacing has additional biological effects. Methods: We monitored cardiac rhythm for 4 weeks after human mesenchymal stem cell transplantation (1 x 10(7), epicardial injection) in 18 dogs in vivo, seven human mesenchymal stem cell with pacing, six human mesenchymal stem cell, and five sham, and evaluated the sympathetic innervation, nerve growth factor-beta; tyrosine hydroxylase, angiogenesis, von Willebrand factor, and connexin43 expressions by real time (RT) polymerase chain reaction and immunostaining. We also measured mRNA expressions of nerve growth factor-beta, von Willebrand factor, and connexin43 in vitro culture of human mesenchymal stem cell with or without pacing. Results: Human mesenchymal stem cell transplanted hearts expressed higher mRNA of nerve growth factor-beta (p < 0.01) with sympathetic nerves (p < 0.05), higher mRNA of von Willebrand factor (p < 0.001.) with angiogenesis (p < 0.001), but lower mRNA of connexin43 (p < 0.0001) with reduced gap junctions (p < 0.001) than sham. Pacing with human mesenchymal stem cell transplantation resulted in higher expression of mRNA of connexin43 (p < 0.02) and gap junctions (p < 0.001) compared with sham. In contrast, in vitro paced mesenchymal stem cell reduced expression of connexin43 mRNA (p < 0.02). Conclusion: Human mesenchymal stem cell transplantation increased cardiac sympathetic innervation and angiogenesis, but reduced gap junction after transplanted in the canine heart. In contrast, concomitant electrical pacing increased gap junction expression by paracrine action.