Circulation Research RES Human Engineered Heart Muscles Engraft and Survive Long-Term in a Rodent Myocardial Infarction Model Engraftment and Survival of Human EHMs CIRCRES/2015/306985 CIRCRES/2015/306985 10.1161/CIRCRESAHA.115.306985 117 09/25/15 8 Bridges-Lyman Gemma 410-3275005 410-3279322 Sussman, Mark San Diego State University Prof. Joseph C Wu joewu@stanford.edu Prof. Stanford University School of Medicine 265 Campus Drive, Room G1120B Stanford California 94305-5454 UNITED STATES 650-736-2246 650-736-0234 7244 Johannes Riegler Stanford University School of Medicine j.riegler@stanford.edu 283654 Malte Tiburcy Georg August University Göttingen m.tiburcy@med.uni-goettingen.de 207615 Antje Ebert Stanford University School of Medicine aebert@stanford.edu 92746 Evangeline Tzatzalos Stanford University School of Medicine etzatza@stanford.edu 257517 Uwe Raaz Stanford University School of Medicine uwe.raaz@gmail.com 289779 Oscar J Abilez Stanford University School of Medicine ojabilez@stanford.edu 164893 Qi Shen Stanford University School of Medicine qishen@stanford.edu 182966 Nigel G Kooreman Stanford University School of Medicine kooreman@stanford.edu 92752 Evgenios Neofytou Stanford University School of Medicine neofytou@stanford.edu 125651 Vincent Chen Beckman Research Institute cychen@coh.org 270798 Mouer Wang Stanford University School of Medicine mouerw@stanford.edu 270802 Tim Meyer Georg August University Göttingen tim.meyer@med.uni-goettingen.de 270803 Philip S Tsao Stanford University School of Medicine ptsao@stanford.edu 3370 Andrew J Connolly Stanford University School of Medicine aconnoll@stanford.edu 174225 Larry A Couture Beckman Research Institute LCouture@coh.org 270805 Joseph D Gold Stanford University School of Medicine jdgold@stanford.edu 92755 Wolfram Hubertus Zimmermann Georg August University Göttingen w.zimmermann@med.uni-goettingen.de 15097 Joseph C Wu Stanford University School of Medicine joewu@stanford.edu 7244 06/09/2015 06/09/2015 08/16/2015 08/19/2015 08/20/2015 09/25/2015 Regular Article cardiac function cell survival engineered heart muscle human embryonic stem cells myocardial infarction <p><i><b><u>Rationale:</u></b></i> Tissue engineering approaches may improve survival and functional benefits from human embryonic stem cell-derived cardiomyocte (ESC-CM) transplantation, thereby potentially preventing dilative remodelling and progression to heart failure. </p><p><i><b><u>Objective:</u></b></i> Assessment of transport stability, long term survival, structural organisation, functional benefits, and teratoma risk of engineered heart muscle (EHM) in a chronic myocardial infarction (MI) model. </p><p><i><b><u>Methods and Results:</u></b></i> We constructed EHMs from ESC-CMs and released them for transatlantic shipping following predefined quality control criteria. Two days of shipment did not lead to adverse effects on cell viability or contractile performance of EHMs (n=3, P=0.83, P=0.87). After ischemia / reperfusion (I/R) injury, EHMs were implanted onto immunocompromised rat hearts at 1 month to simulate chronic ischemia. Bioluminescence imaging (BLI) showed stable engraftment with no significant cell loss between week 2 and 12 (n=6, P=0.67), preserving up to 25% of the transplanted cells. Despite high engraftment rates and attenuated disease progression (change in ejection fraction for EHMs -6.7±1.4% vs control -10.9±1.5%, n>12, P=0.05), we observed no difference between EHMs containing viable or non-viable human cardiomyocytes in this chronic xenotransplantation model (n>12, P=0.41). Grafted cardiomyocytes showed enhanced sarcomere alignment and increased connexin 43 expression at 220 days after transplantation. No teratomas or tumors were found in any of the animals (n=14) used for long-term monitoring. </p><p><i><b><u>Conclusions:</u></b></i> EHM transplantation led to high engraftment rates, long term survival, and progressive maturation of human cardiomyocytes. However, cell engraftment was not correlated with functional improvements in this chronic MI model. Most importantly, the safety of this approach was demonstrated by the lack of tumor or teratoma formation. </p> 0 0 0 5 5 no yes CircRes_CIRCRES-2015-306985.xml CircRes_CIRCRES-2015-306985_file1.docx

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CircRes_CIRCRES-2015-306985_merge.pdf CircRes_CIRCRES-2015-306985_Neofytou_125651_disclosure.pdf CircRes_CIRCRES-2015-306985_Neofytou_125651_copyright.pdf CircRes_CIRCRES-2015-306985_Abilez_164893_disclosure.pdf CircRes_CIRCRES-2015-306985_Abilez_164893_copyright.pdf CircRes_CIRCRES-2015-306985_Tsao_3370_disclosure.pdf CircRes_CIRCRES-2015-306985_Tsao_3370_copyright.pdf CircRes_CIRCRES-2015-306985_Riegler_283654_disclosure.pdf CircRes_CIRCRES-2015-306985_Riegler_283654_copyright.pdf CircRes_CIRCRES-2015-306985_Raaz_289779_disclosure.pdf CircRes_CIRCRES-2015-306985_Raaz_289779_copyright.pdf CircRes_CIRCRES-2015-306985_Couture_270805_disclosure.pdf CircRes_CIRCRES-2015-306985_Couture_270805_copyright.pdf CircRes_CIRCRES-2015-306985_Tiburcy_207615_disclosure.pdf CircRes_CIRCRES-2015-306985_Tiburcy_207615_copyright.pdf CircRes_CIRCRES-2015-306985_Meyer_270803_disclosure.pdf CircRes_CIRCRES-2015-306985_Meyer_270803_copyright.pdf CircRes_CIRCRES-2015-306985_Kooreman_92752_disclosure.pdf CircRes_CIRCRES-2015-306985_Kooreman_92752_copyright.pdf CircRes_CIRCRES-2015-306985_Wang_270802_disclosure.pdf CircRes_CIRCRES-2015-306985_Wang_270802_copyright.pdf CircRes_CIRCRES-2015-306985_Chen_270798_disclosure.pdf CircRes_CIRCRES-2015-306985_Chen_270798_copyright.pdf CircRes_CIRCRES-2015-306985_Ebert_92746_disclosure.pdf CircRes_CIRCRES-2015-306985_Ebert_92746_copyright.pdf CircRes_CIRCRES-2015-306985_Tzatzalos_257517_disclosure.pdf CircRes_CIRCRES-2015-306985_Tzatzalos_257517_copyright.pdf CircRes_CIRCRES-2015-306985_Zimmermann_15097_disclosure.pdf CircRes_CIRCRES-2015-306985_Zimmermann_15097_copyright.pdf CircRes_CIRCRES-2015-306985_Gold_92755_disclosure.pdf CircRes_CIRCRES-2015-306985_Gold_92755_copyright.pdf CircRes_CIRCRES-2015-306985_Shen_182966_disclosure.pdf CircRes_CIRCRES-2015-306985_Shen_182966_copyright.pdf CircRes_CIRCRES-2015-306985_Wu_7244_disclosure.pdf CircRes_CIRCRES-2015-306985_Wu_7244_copyright.pdf CircRes_CIRCRES-2015-306985_Connolly_174225_disclosure.pdf CircRes_CIRCRES-2015-306985_Connolly_174225_copyright.pdf PAP: 08/19/15 Please note that the authors have agreed to pay $425 in excess page charges. Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: Yes Wellcome Trust: No Subject Codes: [130] Animal models of human disease [148] Heart failure - basic studies [150] Imaging [37] CV surgery [105] Contractile function gbridgeslyman