Human Engineered Heart Muscles Engraft and Survive Long-Term in a Rodent Myocardial Infarction Model
Rationale: 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.
Objective: 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.
Methods and Results: 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.
Conclusions: 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.
- human embryonic stem cells
- engineered heart muscle
- myocardial infarction
- cell survival
- cardiac function
- stem cell
- myocardial ischemia
- tissue engineering
- cardiac magnetic resonance imaging
- Received June 9, 2015.
- Revision received August 16, 2015.
- Accepted August 19, 2015.