Cardiology in the Young

Original Articles

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

Sook Kyoung Kima1, Hui-Nam Paka1 c1, Jae Hyung Parka1, Yong Fu Fanga2, Gwang Il Kima3, Yong Doo Parka4, Chun Hwanga5, Young-Hoon Kima2 and Byung Soo Kima6

a1 Department of Cardiology, Yonsei University Health System, Seoul, Korea

a2 Department of Cardiology, Korea University Cardiovascular Center, Seoul, Korea

a3 Department of Pathology, College of Medicine, Pochon CHA University, Seoul, Korea

a4 Department of Biomedical Engineering, Korea University, Seoul, Korea

a5 Utah Valley Medical Center, Provo, UT, United States of America

a6 Department of Hematology, Korea University, Seoul, Korea

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 × 107, 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-β; 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-β, 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-β (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.

(Received September 22 2009)

(Accepted January 10 2010)

(Online publication March 29 2010)

Correspondence:

c1 Correspondence to: H.-N. Pak, MD, PhD, 250 Seungsanno, Seodaemu, Seoul, Republic of Korea 120-752. Tel: +82 2 –2228 58459; Fax: +82 2 393 2041; E-mail: hnpak@yuhs.ac