Thorac Cardiovasc Surg 2013; 61 - OP89
DOI: 10.1055/s-0032-1332328

Co-transplantation of ips-derived cardiomyocytes and mesenchymal stem cells reduce infarct scar size in small animal model of myocardial infarction

YH Choi 1, K Neef 1, F Drey 1, V Lepperhof 2, T Saric 2, OJ Liakopoulos 1, N Madershahian 1, T Wittwer 1, T Wahlers 1
  • 1Herzzentrum der Universität zu Köln, Klinik für Herz-, und Thoraxchirurgie, Köln, Germany
  • 2Universität zu Köln, Institut für Neurophysiologie, Köln, Germany

Introduction: The combined transplantation of mesenchymal stem cells (MSC), mediating paracrine effects, together with cardiomyocytes generated from induced pluripotent cells (iPS-CM), mediating functional effects, holds great promise in cardiac cell therapy. The goal of this study was to analyze how functional improvement of infarcted hearts is mediated on a histological level in a small animal model.

Methods: iPS-CM were generated from a cardiac specific iPS cell line and murine MSC were isolated from bone marrow. iPS-CM, MSC or a combination of both were intramyocardially transplanted to a mouse model of myocardial infarction. Functional cardiac parameters were assessed by magnetic resonance imaging over the course of four weeks. Immunohistochemical analyses were used to quantify sizes of grafts of transplanted MSC and/or iPS-CM. The expansion of infarct scars was quantified four weeks after infarct inductions and cell transplantations. Expression of cardiac specific markers α-actinin 2 and connexin 43 was assessed in grafts of transplanted cells.

Results: The purity of iPS-CM preparations was confirmed flowcytometrically to be > 85%. MSC were validated for expression of CD29 (99.9 ± 0.1%), CD44 (64.1 ± 4.1%) and Sca-1 (98.1 ± 0.9%). Analyses of cardiac function showed significantly higher left-ventricular ejection fraction after four weeks for animals having received co-transplantations (sham: 44.2 ± 2.6%; iPS: 52.0 ± 2.6%; MSC: 47.6 ± 2.1%; iPS+MSC: 52.0 ± 2.6%; iPS-CM+MSC vs. other groups: p < 0.05). Immunohistochemical analyses of graft volumes showed that MSC retention and survival was significantly higher after four weeks compared to iPS-CM graft volumes after four weeks (0.095 ± 0.057 mm3 vs. 0.006 ± 0.004 mm3; p < 0.05). The size of the infarction scar was significantly smaller in the iPS-CM (2.77 ± 1.35 mm2) and the iPS-CM+MSC (2.73 ± 1.18 mm2) groups when compared to the MSC (4.9 ± 1.79 mm2, both p < 0.05) and sham groups (5.73 ± 2.68 mm2, both p < 0.05). Structural maturation of iPS-CM was shown by expression of α-actinin and connexin 43, most prominently on the border zones of grafts and host cardiac tissue.

Conclusion: Intramyocardial co-transplantation of iPS-CM and MSC into infarcted hearts resulted in improved recovery of cardiac function and reduction of infarct scar as compared to single cell type transplantations. This demonstrates the potential of combined transplantations of functional cardiac cells with supporting adult stem cells for regenerative therapies.