Impact of active force development from transplanted engineered heart tissue on left ventricular function

• Applicant: Dr. Florian Weinberger
• Subject Area: Pharmacology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 407066372

The regenerative capacity of the adult heart is very limited and myocardial infarct leads to an irreversible loss of vital myocardium. Simultaneously cardiovascular diseases represent the number one cause of death in the western world. Classical pharmacological therapies are not able to generate new myocardium and currently heart transplantation is the only curative therapy. Regenerative strategies might represent a new approach, especially for patients with severe heart failure. We have established a model to generate three-dimensional heart tissue constructs (engineered heart tissue, EHT) in our Institute. EHTs are generated from cardiomyocytes and a fibrin matrix. Recent progress in stem cell biology allows the differentiation of large numbers of human cardiomyocytes from pluripotent stem cells (embryonic stem cells and induced pluripotent stem cells). This progress enabled the generation of human EHTs (hEHTs). We have recently shown that the transplantation of hEHTs in a cryoinjury model in the guinea pig led to a partial remuscularization of the scar and an increase in left-ventricular function. Remarkably the increase in left-ventricular function was on average greater than the degree of remuscularization. This finding raises the question whether the contribution of the active contraction of the transplanted hEHTs is responsible for the increase in left-ventricular function or whether the improvement rather results from paracrine effects. The proposed project aims to evaluate this central question of regenerative cardiology.We propose three different strategies that should result in an inducible stop of active cardiomyocyte contraction. We plan to investigate these in vitro with the EHT system. The most successful strategy will then be evaluated in an animal model.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Thomas Eschenhagen