Generation of a vascularised heart patch for cardiac regeneration

用于心脏再生的血管化心脏补片的生成

• 批准号: 538972231
• 负责人: Dr. Maria Köhne, Ph.D.
• 金额: --
• 依托单位: Wellcome - MRC Cambridge Stem Cell Institute
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/538972231?language=en
• 关键词: Generation; vascularised; heart; patch; cardiac

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.

在过去的20年里，干细胞来源的心肌细胞(CMS)移植已经成为心力衰竭患者的一种潜在的新的治疗选择。效果已经在小动物和大动物模型中得到了证明。一种方法是移植体外工程心脏组织(EHT)补片。虽然EHT移植已被证明能显著改善心肌梗死(MI)后的心功能，但移植物的大小和相关的功能改善仍然相对较小。这种方法的一个问题是移植后功能细胞的高度损失。原因是移植后直接供氧不足。缺失或非常缓慢的血管形成会导致移植中的大部分细胞死亡。申请该项目的目的是促进移植组织在移植后立即进行有效和可行的血管化。为此，将利用潜在的促血管生成的心外膜细胞(EPI)和内皮细胞(ECs)进行多细胞方法的生成，每一种细胞在胚胎发育过程中对心脏的血管形成和成熟都起着重要作用。辛哈教授的研究小组的初步工作表明，CMS与EPIS共移植可以改善心脏功能，促进组织中心肌细胞的成熟，并增加受体的血管生成。此外，还开发了一种新的冻干胶原补片基质，该基质在鸡胚胎中被血管化，并在加入CMS后改善了大鼠心肌梗死模型的心功能。在前期工作的基础上，该项目将生产一种多细胞EHT贴片，具有合适的载体基质和优化的血管形成潜力。为此，首先将在共培养中优化三种细胞类型(Epis，ECs，CMS)的组成。随后，将在不同的载体材料上测试合适的共培养，以确定哪种基质提供了最好的细胞存活性能。为此，EHT将被移植到成年大鼠的背部。如果血管形成成功，细胞存活得到证实，EHTS将被移植到受损的大鼠心脏上，研究优化的EHT贴片是否可以形成血管并显著提高心功能。该项目将展示多细胞EHT贴片中不同细胞类型对血管形成、成熟、功能以及这种结构的生物学相关性的影响。因此，该项目对心脏再生治疗领域的知识和进步做出了重要贡献。