Inherited cardiac diseases, pluripotent stem cells, and genome editing combined—the past, present, and future

• Published in: Stem cells (Dayton, Ohio) Ohio), 2020-02, Vol.38 (2), p.174-186
• Main Authors: Brink, Lettine, Grandela, Catarina, Mummery, Christine L., Davis, Richard P.
• Format: Article
• Language: English
• Subjects: cardiac; Cardiomyocytes; Cardiovascular diseases; Cell Differentiation; Concise Review; Concise Reviews; Coronary artery disease; CRISPR; differentiation; Disease; Disease control; Editing; Etiology; experimental models; Gene Editing - methods; gene targeting; Genetic diversity; Genetic variance; Genome editing; Genomes; Genotypes; Health risks; Heart diseases; Heart Diseases - congenital; Humans; Mutants; Mutation; Pathogenesis; Patients; Phenotypes; Pluripotency; pluripotent stem cells; Pluripotent Stem Cells - metabolism; Risk management; Stem cell transplantation; Stem cells
• ISSN: 1066-5099; 1549-4918
• DOI: 10.1002/stem.3110

Research on mechanisms underlying monogenic cardiac diseases such as primary arrhythmias and cardiomyopathies has until recently been hampered by inherent limitations of heterologous cell systems, where mutant genes are expressed in noncardiac cells, and physiological differences between humans and experimental animals. Human‐induced pluripotent stem cells (hiPSCs) have proven to be a game changer by providing new opportunities for studying the disease in the specific cell type affected, namely the cardiomyocyte. hiPSCs are particularly valuable because not only can they be differentiated into unlimited numbers of these cells, but they also genetically match the individual from whom they were derived. The decade following their discovery showed the potential of hiPSCs for advancing our understanding of cardiovascular diseases, with key pathophysiological features of the patient being reflected in their corresponding hiPSC‐derived cardiomyocytes (the past). Now, recent advances in genome editing for repairing or introducing genetic mutations efficiently have enabled the disease etiology and pathogenesis of a particular genotype to be investigated (the present). Finally, we are beginning to witness the promise of hiPSC in personalized therapies for individual patients, as well as their application in identifying genetic variants responsible for or modifying the disease phenotype (the future). In this review, we discuss how hiPSCs could contribute to improving the diagnosis, prognosis, and treatment of an individual with a suspected genetic cardiac disease, thereby developing better risk stratification and clinical management strategies for these potentially lethal but treatable disorders. Key phenotypic features of inherited cardiac diseases that are seen in patients are often detected in the corresponding human‐induced pluripotent stem cell‐derived cardiomyocytes (past). Now (present), genome editing tools enable disease genotype‐phenotype relationships to be investigated. In the future, this could aid in identifying both pathogenic and disease‐modifying genetic variants, and potentially contribute to improvements in diagnosis, prognosis, and treatment of patients.