Thorac Cardiovasc Surg 2014; 62 - SC7
DOI: 10.1055/s-0034-1367268

Different degrees of protective effect by types of fibroblasts on induced pluripotent stem cell-derived cardiomyocytes in bioartificial cardiac tissue in vivo

S. Saito 1, G. Kensah 1, H. Baraki 1, J. Dahlmann 1, A. Haverich 2, J. Hundrieser 3, U. Martin 2, I. Gruh 2, I. Kutschka 1
  • 1Universitätsklinikum der Otto-von-Guericke-Universität Magdeburg, Klinik für Herz- und Thoraxchirurgie, Magdeburg, Germany
  • 2Medizinische Hochschule Hannover, Klinik für Herz-, Thorax-, Transplantations- und Gefäßchirurgie, Hannover, Germany
  • 3Medizinische Hochschule Hannover, Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Hannover, Germany

Objectives: It is well known that the presence of supporting non-cardiac cells such as fibroblasts is crucial for survival and coupling of the pluripotent stem cell-derived cardiomyocytes in bioartificial cardiac tissue (BCT) in vitro, and different types of fibroblasts may differently affect the cardiomyocyte physiology. The aim of this study is to evaluate the protective effects of the different types of fibroblasts on cardiomyocytes within BCT in vivo.

Methods: BCT was prepared from a mixture of liquid collagen type I and Matrigel combined with mouse induced pluripotent stem cell-derived cardiomyocytes (miPSC-CMs) and γ-irradiated fibroblasts (10% of miPSC-CMs). As fibroblasts, human foreskin fibroblasts were used in Group-Xeno (n = 10) and mouse fetal fibroblasts were used in Group-Pure (n = 10). BCTs were implanted in the heart of nude rats with chronic myocardial infarction. As control groups, rats received human foreskin fibroblast-BCT without miPSC-CMs (n = 5), mouse fetal fibroblast-BCT without miPSC-CMs (n = 5), or sham operation (n = 10). The heart function was monitored by serial echocardiography and magnetic resonance imaging (MRI). The hearts were explanted 4 weeks after the implantation and histological examinations were performed. α-Actinin staining was done and the survival of miPSC-CMs was evaluated as the percentage of α-Actinin positive area to BCT area (%α-Actinin area). CD31 staining was done and (1) the number of vessels in the area between host myocardium and BCT and (2) the number of vessels within BCT were counted. Vascularity was evaluated as {(1) + (2)} / BCT area (/mm2, vascularity index).

Results: After BCT implantation, the heart function was the best preserved in Group-Xeno (fractional shortening: repeated measures ANOVA p = 0.002, Xeno 29.1 ± 5.0%, Pure 22.6 ± 7.5% at 4 weeks). At 4 weeks after the implantation, survival of cardiomyocytes within BCT (%α-Actinin area) was significantly higher in Group-Xeno than in Group-Pure (29.0 ± 4.9% vs. 9.5 ± 6.5%, p  < 0.001). Vascularity index was also significantly higher in Group-Xeno than in Group-Pure (13.8 ± 5.6 vs. 3.9 ± 3.7 /mm2, p = 0.002).

Conclusion: Human foreskin fibroblast supplemented in BCT induced more neovascularization and resulted in higher survival of miPSC-CMs in BCT in vivo than mouse fetal fibroblasts, which resulted in higher beneficial effects on heart function.