Generation of a vascularised heart patch for cardiac regeneration

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The transplantation of stem cell-derived cardiomyocytes (CMs) has emerged as a potentially novel therapy option for heart failure patients within the past 20 years. Efficacy has been demonstrated in both small and large animal models. One approach is the transplantation of in vitro engineered heart tissue (EHT) patches. Although transplantation of EHT has been shown to significantly improve cardiac function after myocardial infarction (MI), but the size of the grafts and the associated functional improvement remains relatively small. One problem with this approach is the high loss of functional cells after transplantation. The reason for this is the lack of oxygen supply directly after transplantation. The missing or very slow vascularisation leads to the death of a large part of the cells in the transplant. The project applied for here aims to promote efficient and practically feasible vascularisation of the tissue immediately after transplantation. For this purpose, the generation of a multicellular approach will be pursued with potentially proangiogenic epicardial cells (EPIs) and endothelial cells (ECs), each playing an important role in vascularisation and maturation of the heart during embryological development. Preliminary work by Prof. Sinha's group has shown that co-transplantation of CMs with EPIs promotes improved cardiac function, maturation of cardiomyocytes in the tissue and increased vascularisation on the part of the recipient. In addition, a new patch matrix of freeze-dried collagen was developed, which was vascularised in the chicken embryo and improved cardiac function in the rat MI model after incorporation of CMs. Based on this preliminary work, this project will produce a multicellular EHT patch with a suitable carrier matrix and optimised vascularisation potential. For this purpose, the composition of three cell types (EPIs, ECs, CMs) will first be optimised in a co-culture. Subsequently, the suitable co-culture will be tested on different carrier materials to determine which of the matrices offers the best properties for cell survival. For this purpose, the EHT will be transplanted subcutaneously into the dorsum of adult rats. If vascularisation is successful and cell survival can be confirmed, EHTs will be transplanted onto injured rat hearts in a study to investigate whether the optimised EHT patches can vascularise and significantly increase cardiac function. This project will demonstrate the influence of different cell types in a multicellular EHT patch on vascularisation, maturation, function and thus the biological relevance of such a construct. This project thus makes an important contribution to knowledge and progress in the field of cardiac regenerative therapy.