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Published online 5 September 2006 doi:10.1084/jem.20061469
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2315-2327
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ARTICLE

 Engraftment of engineered ES cell–derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium

Eugen Kolossov1, Toktam Bostani2, Wilhelm Roell3, Martin Breitbach2, Frank Pillekamp4,6, Jens M. Nygren7, Philipp Sasse2, Olga Rubenchik4, Jochen W. U. Fries5, Daniela Wenzel2, Caroline Geisen2, Ying Xia4, Zhongju Lu4, Yaqi Duan4, Ralf Kettenhofen1, Stefan Jovinge7, Wilhelm Bloch8, Heribert Bohlen1, Armin Welz3, Juergen Hescheler4, Sten Eirik Jacobsen7, and Bernd K. Fleischmann2

1 Axiogenesis AG, 50931 Cologne, Germany
2 Institute of Physiology I and 3 Department of Cardiac Surgery, University of Bonn, 53105 Bonn, Germany
4 Institute of Neurophysiology, 5 Department Pathology, and 6 Department of Pediatric Cardiology, University of Cologne, 50931 Cologne, Germany
7 Hematopoietic Stem Cell Laboratory, Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, 221 00 Lund, Sweden
8 German Sports University, 50927 Cologne, Germany

CORRESPONDENCE Bernd K. Fleischmann: bernd.fleischmann{at}uni-bonn.de OR Eugen Kolossov: eugen.kolossov{at}axiogenesis.com

Cellular cardiomyoplasty is an attractive option for the treatment of severe heart failure. It is, however, still unclear and controversial which is the most promising cell source. Therefore, we investigated and examined the fate and functional impact of bone marrow (BM) cells and embryonic stem cell (ES cell)–derived cardiomyocytes after transplantation into the infarcted mouse heart. This proved particularly challenging for the ES cells, as their enrichment into cardiomyocytes and their long-term engraftment and tumorigenicity are still poorly understood. We generated transgenic ES cells expressing puromycin resistance and enhanced green fluorescent protein cassettes under control of a cardiac-specific promoter. Puromycin selection resulted in a highly purified (>99%) cardiomyocyte population, and the yield of cardiomyocytes increased 6–10-fold because of induction of proliferation on purification. Long-term engraftment (4–5 months) was observed when co-transplanting selected ES cell–derived cardiomyocytes and fibroblasts into the injured heart of syngeneic mice, and no teratoma formation was found (n = 60). Although transplantation of ES cell–derived cardiomyocytes improved heart function, BM cells had no positive effects. Furthermore, no contribution of BM cells to cardiac, endothelial, or smooth muscle neogenesis was detected. Hence, our results demonstrate that ES-based cell therapy is a promising approach for the treatment of impaired myocardial function and provides better results than BM-derived cells.

Abbreviations used: {alpha}-MHC, {alpha}–myosin heavy chain; ASMAC, {alpha}–smooth muscle actin; EB, embryoid body; EGFP, enhanced GFP; ES cell, embryonic stem cell; LCA, left coronary artery; LVEF, left ventricular ejection fraction; LVF, left ventricular function; MEA, microelectrode array; PECAM, platelet/endothelial cell adhesion molecule.

E. Kolossov, T. Bostani, W. Roell, and M. Breitbach contributed equally to this work.


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