Hoffmann Sandra, Seeger Timon
University Hospital Heidelberg Institute of Human Genetics Heidelberg Germany.
Med Genet. 2025 Apr 8;37(2):137-146. doi: 10.1515/medgen-2025-2009. eCollection 2025 Jun.
Human induced pluripotent stem cell (hiPSC)-based disease modelling has significantly advanced the field of cardiogenetics, providing a precise, patient-specific platform for studying genetic causes of heart diseases. Coupled with genome editing technologies such as CRISPR/Cas, hiPSC-based models not only allow the creation of isogenic lines to study mutation-specific cardiac phenotypes, but also enable the targeted modulation of gene expression to explore the effects of genetic and epigenetic deficits at the cellular and molecular level. hiPSC-based models of heart disease range from two-dimensional cultures of hiPSC-derived cardiovascular cell types, such as various cardiomyocyte subtypes, endothelial cells, pericytes, vascular smooth muscle cells, cardiac fibroblasts, immune cells, etc., to cardiac tissue cultures including organoids, microtissues, engineered heart tissues, and microphysiological systems. These models are further enhanced by multi-omics approaches, integrating genomic, transcriptomic, epigenomic, proteomic, and metabolomic data to provide a comprehensive view of disease mechanisms. In particular, advances in cardiovascular tissue engineering enable the development of more physiologically relevant systems that recapitulate native heart architecture and function, allowing for more accurate modelling of cardiac disease, drug screening, and toxicity testing, with the overall goal of personalised medical approaches, where therapies can be tailored to individual genetic profiles. Despite significant progress, challenges remain in the maturation of hiPSC-derived cardiomyocytes and the complexity of reproducing adult heart conditions. Here, we provide a concise update on the most advanced methods of hiPSC-based disease modelling in cardiogenetics, with a focus on genome editing and cardiac tissue engineering.
基于人诱导多能干细胞（hiPSC）的疾病建模极大地推动了心脏遗传学领域的发展，为研究心脏病的遗传病因提供了一个精确的、针对患者的平台。结合CRISPR/Cas等基因组编辑技术，基于hiPSC的模型不仅能够创建同基因系来研究特定突变的心脏表型，还能实现基因表达的靶向调控，以在细胞和分子水平探索遗传和表观遗传缺陷的影响。基于hiPSC的心脏病模型范围广泛，从hiPSC衍生的心血管细胞类型（如各种心肌细胞亚型、内皮细胞、周细胞、血管平滑肌细胞、心脏成纤维细胞、免疫细胞等）的二维培养，到包括类器官、微组织、工程心脏组织和微生理系统在内的心脏组织培养。通过多组学方法进一步增强了这些模型，整合基因组、转录组、表观基因组、蛋白质组和代谢组数据，以全面了解疾病机制。特别是，心血管组织工程的进展使得能够开发出更具生理相关性的系统，重现天然心脏结构和功能，从而更准确地模拟心脏病、进行药物筛选和毒性测试，总体目标是实现个性化医疗方法，即根据个体遗传特征定制治疗方案。尽管取得了重大进展，但在hiPSC衍生心肌细胞的成熟以及重现成人心脏状况的复杂性方面仍存在挑战。在此，我们简要介绍心脏遗传学中基于hiPSC的疾病建模的最先进方法，重点关注基因组编辑和心脏组织工程。
