Parthenogenetic stem cells for tissue- engineered heart repair

Michael, Didié, Peter, Christalla, Michael, Rubart, Vijayakumar, Muppala, Stephan, Döker, Bernhard, Unsöld, Ali, El-Armouche, Thomas, Rau, Thomas, Eschenhagen, Alexander P, Schwoerer, Heimo, Ehmke, Udo, Schumacher, Sigrid, Fuchs, Claudia, Lange, Alexander, Becker, Wen, Tao, John A, Scherschel, Mark H, Soonpaa, Tao, Yang, Qiong, Lin, Martin, Zenke, Dong-wook, Han, Hans R, Schöler, Cornelia, Rudolph, Doris, Steinemann, Brigitte, Schlegelberger, Steve, Kattman, Alec, Witty, Gordon, Keller, Loren J, Field, Wolfram-Hubertus, Zimmermann

Journal of Clinical Investigation |

Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenoge- netic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar funda- mental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocom- patibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documen- tation of advanced structural and functional maturation in vitro and in vivo. This included seamless electri- cal integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyo- cytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.