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

移植的工程心脏组织产生主动力对左心室功能的影响

• 批准号: 407066372
• 负责人: Dr. Florian Weinberger
• 金额: --
• 依托单位: Institut für Experimentelle Pharmakologie und Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407066372?language=en
• 关键词: Impact; active; force; development; transplanted

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.

成人心脏的再生能力非常有限，心肌梗塞会导致重要心肌的不可逆转的损失。同时，心血管疾病是西方世界的第一大死因。经典的药物疗法无法产生新的心肌，目前心脏移植是唯一的治疗方法。再生策略可能代表一种新方法，特别是对于患有严重心力衰竭的患者。我们在我们的研究所建立了一个模型来生成三维心脏组织结构（工程心脏组织，EHT）。 EHT 由心肌细胞和纤维蛋白基质产生。干细胞生物学的最新进展允许从多能干细胞（胚胎干细胞和诱导多能干细胞）分化出大量的人类心肌细胞。这一进展使得人类 EHT（hEHT）的产生成为可能。我们最近发现，在豚鼠冷冻损伤模型中移植 hEHT 可以导致疤痕部分重新肌肉化，并增强左心室功能。值得注意的是，左心室功能的平均增加程度大于肌再化程度。这一发现提出了一个问题：移植的 hEHT 的主动收缩是否是左心室功能增强的原因，或者这种改善是否是旁分泌效应的结果。 拟议的项目旨在评估再生心脏病学的这一核心问题。我们提出了三种不同的策略，应导致主动心肌细胞收缩的诱导停止。我们计划使用 EHT 系统在体外研究这些。然后将在动物模型中评估最成功的策略。