Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts

• Published in: Nature biotechnology 2007-09, Vol.25 (9), p.1015-1024
• Main Authors: Murry, Charles E, Laflamme, Michael A, Chen, Kent Y, Naumova, Anna V, Muskheli, Veronica, Fugate, James A, Dupras, Sarah K, Reinecke, Hans, Xu, Chunhui, Hassanipour, Mohammad, Police, Shailaja, O'Sullivan, Chris, Collins, Lila, Chen, Yinhong, Minami, Elina, Gill, Edward A, Ueno, Shuichi, Yuan, Chun, Gold, Joseph
• Format: Article
• Language: English
• Subjects: Agriculture; Animals; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cardiovascular disease; Cell Differentiation; Cell Movement; Cell Survival; Echocardiography; Embryonic Stem Cells - cytology; Fundamental and applied biological sciences. Psychology; Graft Survival; Health. Pharmaceutical industry; Heart attacks; Heart Ventricles - metabolism; Humans; Industrial applications and implications. Economical aspects; Life Sciences; Magnetic Resonance Imaging; Male; Miscellaneous; Myocardial infarction; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - pathology; Myocytes, Cardiac - cytology; Myocytes, Cardiac - transplantation; Rats; Rats, Sprague-Dawley; Rodents; Skin & tissue grafts; Stem cells; Survival; Transplantation
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1327

Cardiomyocytes derived from human embryonic stem (hES) cells potentially offer large numbers of cells to facilitate repair of the infarcted heart. However, this approach has been limited by inefficient differentiation of hES cells into cardiomyocytes, insufficient purity of cardiomyocyte preparations and poor survival of hES cell–derived myocytes after transplantation. Seeking to overcome these challenges, we generated highly purified human cardiomyocytes using a readily scalable system for directed differentiation that relies on activin A and BMP4. We then identified a cocktail of pro-survival factors that limits cardiomyocyte death after transplantation. These techniques enabled consistent formation of myocardial grafts in the infarcted rat heart. The engrafted human myocardium attenuated ventricular dilation and preserved regional and global contractile function after myocardial infarction compared with controls receiving noncardiac hES cell derivatives or vehicle. The ability of hES cell–derived cardiomyocytes to partially remuscularize myocardial infarcts and attenuate heart failure encourages their study under conditions that closely match human disease.