Hypo-immunogenic cardiomyocytes for myocardial repair

项目摘要 心脏病是西方世界的头号杀手。虽然心脏移植可能有效， 治疗心力衰竭，今天移植最紧迫的问题是缺乏合适的供体器官， 组织中诱导的多能干细胞（iPSC）构成自体患者特异性造血干细胞的潜在来源。 心肌细胞用于心脏修复，在免疫方面提供了优于其他细胞来源的主要益处。 排斥反应然而，自体移植具有与制造相关的实质性挑战， 调控虽然同种异体移植是一种有前途的替代策略，但很少有免疫策略 已经被提出来克服免疫障碍。我们创造了一个低免疫原性小鼠和一个 人类hypo-iPSC细胞系都能逃避免疫排斥，我们已经成功地建立了它们的 在一些实施方案中，所述细胞可以分化为小鼠心肌细胞（mCM）和人心脏细胞（hCC）。拟定研究 分为三个组分，以充分证明我们产生的iPSC的低免疫原性。第一 本研究的第二个目的是研究接受同种异体移植的宿主的免疫激活， mCMs/hypo-mCMs或同种异体hCCs/hypo-hCCs，以及对植入的hCCs/hypo-hCCs的存活率的评估。 细胞随着时间的推移。将利用最先进的免疫学和成像技术来证明免疫 激活和细胞存活。第三个目标是研究hypo-hCCs增加肌肉再生的能力 并使用非人灵长类动物增强衰竭心肌的功能性能 心肌缺血-再灌注和心肌内递送hCC的模型。 这项研究的成功完成将为克服iPSC中的免疫生物学屏障提供深入了解。 应用和hypo-hCCs在支持功能恢复失败的潜在适用性 心肌

PROJECT SUMMARY Heart disease is the number one killer in the Western world. Although heart transplant may be effective in treating heart failure, today’s most urgent problem in transplantation is the lack of suitable donor organs and tissues. Induced pluripotent stem cells (iPSCs) constitute a potential source of autologous patient-specific cardiomyocytes for cardiac repair, providing a major benefit over other sources of cells in terms of immune rejection. However, autologous transplantation has substantial challenges related to manufacturing and regulation. Although allogeneic transplantation is a promising alternative strategy, few immunological strategies have been proposed to overcome the immunological hurdle. We created a hypo-immunogenic mouse and a human hypo-iPSC line that both evade immune rejection, and we have successfully established their differentiation into mouse cardiomyocytes (mCMs) and human cardiac cells (hCCs). The proposed study is divided into three components to fully demonstrate the hypo-immunogenicity of our generated iPSCs. The first and second aims of this study is focused on studying the immune activation of the host receiving allogeneic mCMs/hypo-mCMs or allogeneic hCCs/hypo-hCCs, respectively, and on evaluation of the survival of implanted cells over time. State-of-the art immunological and imaging techniques will be utilized to demonstrate immune activation and cell survival. The third aim will investigate the ability of hypo-hCCs to increase remuscularization of the heart and to augment the functional performance of failing myocardium using a non-human primate model of myocardial ischemia-reperfusion and intra-myocardial delivery of hCCs over a three-month period. Successful completion of this study will provide insight into overcoming the immunobiological barrier in iPSC applications and the potential applicability of the hypo-hCCs in supporting functional recovery of failing myocardium.