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

成人心脏的再生能力非常有限，心肌梗死会导致生命心肌不可逆转的丧失。与此同时，心血管疾病是西方世界的头号死因。传统的药物治疗不能产生新的心肌，目前心脏移植是唯一的根治方法。再生策略可能代表着一种新的方法，特别是对于患有严重心力衰竭的患者。我们在我们研究所建立了一个生成三维心脏组织结构(工程化心脏组织，EHT)的模型。EHTS是由心肌细胞和纤维蛋白基质产生的。干细胞生物学的最新进展使得从多能干细胞(胚胎干细胞和诱导多能干细胞)分化为大量的人心肌细胞成为可能。这一进展使人类超高温反应(HEHTs)的产生成为可能。我们最近已经证明，在豚鼠的冷冻损伤模型中移植hEHTs导致了瘢痕的部分肌化和左心功能的增加。值得注意的是，平均而言，左心功能的增加程度大于肌化程度。这一发现提出了一个问题：移植的hEHTs的主动收缩是否导致左心功能的增加，或者这种改善是否更多地来自旁分泌效应。这项拟议的项目旨在评估再生心脏病学的这一中心问题。我们提出了三种不同的策略，这些策略应该导致主动心肌细胞收缩的可诱导停止。我们计划用EHT系统在体外对这些进行研究。最成功的策略将在动物模型中进行评估。

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.