MICA:Characterization of graft-host cellular niche and crosstalk to augment cardiomyocyte-based cellular therapy to treat heart failure.

心脏病发作时，心肌死亡，损害心脏的泵血能力。随后出现心力衰竭，确诊后5年内有1 / 2的几率死亡。随着人口老龄化，心力衰竭越来越普遍，目前有多达100万英国公民受到影响。目前，心脏移植是治疗心力衰竭的唯一方法，但在英国每年只有200例左右的心脏移植手术。因此，心力衰竭是一个快速增长的未被满足的临床需求。不幸的是，心脏是人体中繁殖能力最低的器官，无法恢复其泵血功能。干细胞是一种可以转化为体内任何细胞类型的细胞，因此使用干细胞为基础的方法来增加新的心肌，对恢复心脏的泵血能力有很大的希望。以干细胞为基础的心脏细胞已经在动物身上被证明可以恢复一些心肌。心外膜是心脏的外层，对心脏的发育至关重要，因为它为心肌和一些血管提供支持细胞。此外，心外膜细胞不断地与心肌细胞对话。细胞之间这种活跃的来回交流已被证明对哺乳动物心脏的健康发育至关重要。我们最近发现，在心脏病发作后不久，将干细胞来源的心外膜与干细胞来源的心脏细胞结合使用可以改善心脏功能。然而，当心脏病发作很久以前就形成疤痕和心力衰竭时，仅靠干细胞心脏细胞无法改善心脏功能。我们推断，宿主心脏的创伤环境极大地挑战了干细胞衍生的心脏细胞与宿主心脏融合（即移植）的能力。当干细胞衍生的心脏细胞与宿主组织融合良好时，细胞将形成与宿主组织连续性的新心肌。这是成功恢复衰竭心脏泵血功能所必需的。根据我们早期研究的数据，我们假设宿主心脏在试图恢复衰竭的心脏时，会不断地与移植的心脏细胞对话，反之亦然。宿主-移植物之间的交流将能够影响宿主和移植心脏细胞的行为。我们还假设，当不同类型的心脏细胞被引入宿主心脏时，这种交流会被不同的宿主环境（即疤痕）所改变。为了改善衰竭心脏的泵送作用，我们需要在基因组水平上了解宿主-移植物串扰。这将使我们能够改变宿主-移植物的通讯，以改善心脏细胞的植入和恢复心脏的泵血能力。因此，本研究的主要目标是首先确定有和没有细胞治疗的梗死大鼠心脏的独特基因组特征。这将使我们能够了解单个细胞如何相互交谈并改变它们的行为，以响应环境和自身。其次，我们将确定一组小分子，这些小分子将提高干细胞衍生的心脏细胞移植的能力，并恢复心脏的泵血能力。第三，我们的目标是在实验室环境下测试小分子是否会改善心脏细胞在人体心脏组织内的植入。我们还将使用老化和梗死的人体组织来最好地模拟临床试验环境。在实验室中测试人类心脏细胞与复杂人类心脏组织的植入是独一无二的。这使我们有机会在临床试验之前解决任何挑战。总的来说，这个项目是发展干细胞来源的心脏细胞作为一种常见的心力衰竭治疗的关键一步——一种比心脏移植更容易获得的治疗方法。

In a heart attack, the heart muscle dies which impairs the pumping ability of the heart. Heart failure ensues which carries 1 in 2 chances of death within 5 years of diagnosis. With an ageing population, heart failure is increasingly common with up to ~1 million UK citizens affected currently. At this moment, heart transplantation is the only definitive cure for heart failure but only ~200 heart transplants are performed each year in the UK. Thus, heart failure is a rapidly growing unmet clinical need. Unfortunately, the heart is the least replicative organ in the body and is unable to restore its pumping action. Stem cells are cells that can turn into any cell type in the body, and so adding new heart muscle using a stem cell-based approach holds great promise to reinstate the pumping ability of the heart. Stem cell-based heart cells have been shown in animals to restore some heart muscle. The epicardium, the outer layer of the heart, is essential for cardiac development as it contributes to supportive cells of the heart muscle and some blood vessels. Furthermore, the epicardial cells are constantly talking to the cardiac cells. This active to-and-fro communication between cells has been shown to be crucial for healthy heart development in mammals. We recently showed that combining stem cell-derived epicardium in combination with stem cell-derived heart cells improve heart function when delivered shortly after a heart attack. However, stem-cell-based heart cells alone were unable to improve cardiac function when the heart attack was long ago with resultant scarring and heart failure. We reasoned that the host heart's scarred environment greatly challenges the stem cell-derived heart cells' ability to merge well (i.e engraft) with the host heart. When stem cell-derived heart cells merge well with the host tissue, the cells will form new heart muscle in continuity with the host tissue. This is required to successfully restore the pumping action of the failing heart. Based on the data from our early studies, we hypothesized that the host heart is constantly talking to the engrafted heart cells and vice versa, as they attempt to restore the failing heart. The host-graft communication will be able to affect both host's and transplanted heart cells' behaviour. We also hypothesized that this communication is altered by different host environments (i.e. scarred) and when different types of heart cells are introduced into the host heart. So as to improve the pumping action of failing hearts, we need to understand the host-graft crosstalk at the genomic level. This will enable us to alter the host-graft communication, in order to improve the heart cells' engraftment and reinstate the pumping ability of the heart. Thus, the key goals of this study are first to identify the unique genomic signatures of infarcted rat hearts with and without cell therapy. This will enable us to understand how the individual cells are talking to each other and changing their behaviour, in response to the environment and themselves. Secondly, we will identify a panel of small molecules that will improve the ability of the stem cells-derived heart cells to engraft and restore the heart's pumping ability. Thirdly, we aim to test whether the small molecules will improve the heart cells' engraftment within human cardiac tissues in the laboratory setting. We will also use ageing & infarcted human tissues to best simulate the clinical trials setting. Testing the engraftment of human heart cells with complex human heart tissues in the laboratory is unique. This gives us the chance to address any challenges prior to clinical trials. Overall, this project is a key step to developing stem cells-derived heart cells as a commonplace heart failure treatment - a more accessible treatment alternative to heart transplantation.