Generation of four-chambered hearts through organoid fusions

通过类器官融合生成四腔心脏

• 批准号: 10241678
• 负责人: Guang Li
• 金额: $ 140.45万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241678
• 关键词: Anatomy; Cardiac; Cell Line; Congenital Heart Defects; Defect; Development; Diagnosis; Disease; Disease Progression; Disease model; Generations; Genetic; Goals; Heart; Heart Atrium; Heart Septum; Heart Valves; Human; Live Birth; Methods; Modeling; Mus; Mutation; Organoids; Patients; Process; Structure; Techniques; Tissues; Ventricular; base; cardiogenesis; congenital heart disorder; falls; induced pluripotent stem cell; novel; prevent; species difference; success

Project Summary Congenital heart defects (CHDs) account for 1-2% of all live births in the U.S. More than 90% of these diseases are attributed to defects in heart valves and septum; Of which, few have been modeled in mice likely due to species differences and genetic complexities behind the disease. As an alternative approach, human induced pluripotent stem cells (hiPSC), which has demonstrated great success in mimicking other diseases, falls short in the modeling of CHDs, especially in regard to spatial sensitive mechanisms like those involved in heart chamber development. However, with the emergence of organoids, the field is making significant strides toward better CHD models. Currently, the limitations of using organoids resides in the structures integrity when compared to the endogenous tissue, yet, the potential for CHD modelling is unmatched. Here I propose using a novel method based on the organoid fusion principle to generate hearts with anatomically features: chambers, valves and septum. To do this, we will first fuse one atrial and one ventricular organoid to create the cardiac valves. Next, we will further extend this process to advance the formation of the valves and begin formation of the septum by fusing two atrial and two ventricular organoids. Furthermore, we plan to use several of our hiPSC lines either carrying CHD mutations or being directly reprogrammed from patients diagnosed with CHDs to generate fused organoids that will allow us to model the disease progressions in patients. We anticipate that the successful application of these techniques will offer significant improvements in modeling the normal human heart development and congenital heart defects, with the ultimate goal of preventing and treating congenital heart diseases.

项目摘要 先天性心脏缺陷（CHD）占美国所有活产婴儿的1-2%。 疾病归因于心脏瓣膜和隔膜的缺陷;其中，很少在小鼠中建模， 由于疾病背后的物种差异和遗传复杂性。作为替代方法，人类 诱导性多能干细胞（hiPSC）在模拟其他疾病方面取得了巨大成功， 福尔斯在CHD的建模方面存在不足，特别是在空间敏感机制方面，如参与 心室发育然而，随着类器官的出现，该领域正在取得重大进展 更好的CHD模型。目前，使用类器官的局限性在于结构完整性， 与内源性组织相比，CHD建模的潜力是无与伦比的。在这里，我建议使用 一种基于类器官融合原理生成具有解剖学特征的心脏的新方法： 腔室、阀和隔膜。为此，我们将首先融合一个心房和一个心室类器官， 心脏瓣膜接下来，我们将进一步延长这一过程，以推进瓣膜的形成，并开始 通过融合两个心房和两个心室类器官形成隔膜。此外，我们计划使用几个 我们的hiPSC系携带CHD突变或直接从诊断为CHD的患者中重编程， CHD产生融合的类器官，这将使我们能够模拟患者的疾病进展。我们 预计这些技术的成功应用将为建模提供重大改进 人类正常心脏发育和先天性心脏缺陷，最终目的是预防和 治疗先天性心脏病