{"doi":"10.1093/cvr/cvab373","title":"Utilization of induced pluripotent stem cells to model the molecular network regulating congenital heart disease","abstract":"This editorial refers to ‘Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect’ by L. Ye et al., pp. 859–871. Congenital heart disease (CHD) occurs when the atria and ventricles are abnormal during the earlier stages of development, leading to atrial septal defect (ASD), ventricular septal defect, or both. ASD is among the most frequently diagnosed forms of CHD and is typically characterized by left-to-right shunting and increased right ventricular output.1 CHD can result in chronic or acute heart disease depending on the degree of malformation. CHD is the most commonly occurring congenital birth defect. Although technological advances in healthcare have made a difference, children afflicted with CHD are still confronted with significant morbidity and mortality.2,3 Cardiac malformations present at birth are a substantial component of pediatric cardiovascular disease that makes up a considerable percentage of clinically relevant congenital disabilities, occurring in ∼4–50 per 1000 live births.4,5 Recent progress has led to a better understanding of the aetiology of CHD, allowing clinicians to implement new approaches that decrease morbidity and mortality rates among affected infants. Nevertheless, to date, the overall mechanisms that regulate cardiac development leading to CHD remain poorly understood. A powerful novel paradigm in cardiovascular disease modeling is the application of induced pluripotent stem cells (iPSCs) and their differentiated cardiovascular cells to develop in vitro models of human physiology.1,6 iPSCs are a valuable tool for evaluating highly sensitive dysregulation of multiple pathways (e.g. genes associated with heart development, cardiomyocyte function, and CHD genetics) in specific subpopulations of cardiomyocytes.7 Specifically, iPSC-derived cardiomyocytes (iPSC-CMs) have gained popularity as experimental models because they are human derived and readily available and can be cultured in vitro for weeks to months.7 Ye et al.1 used the iPSC-CM model to better elucidate the role of the GATA4–FGF16 axis in promoting the CHD during heart development, as it relates to ASD (Figure 1). GATA4 is a critical transcription factor involved in coordinating heart development. FGF16 belongs to the fibroblast growth factor (FGF) family, containing 22 structurally related members known for cell proliferation, migration, and differentiation in embryonic development.6 To model the GATA4 mutation-associated ASD, both GATA4-mutant iPSCs and embryonic stem cells (ESCs) were differentiated into cardiomyocytes (CMs). In 2010, a study utilized genetic analysis to reveal that the GATA4 T280M mutation is associated with familial ASD in an autosomal dominant inheritance.8 Ye et al.1 built upon this previous study by generating a patient-specific iPSC line (iPSC-G4 T280M) from a family cohort carrying a hereditary ASD mutation in the GATA4 gene (T280M). They also generated a human ESC line (ESC-G4 T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method.1 This study represents the first time that the human iPSC model was used to show the direct relationship between GATA4 T280M and ASD, in which overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect.1 In addition to using the iPSC model to reveal the crosstalk between GATA4 and FGF16, they detected significantly lower DNA occupancy of the GATA4 T280M protein, which disrupts activation or suppression of GATA4-targeted genes in iPSC-G4 T280M-CMs.1 Loss-of-function mutations are the direct causes of GATA4 mutation-induced cardiovascular diseases such as CHD. Application of human-based induced pluripotent stem cells to model congenital heart disease. Utilization of the generation and characterization of patient-specific iPSCs allowed Ye et al. to discover that FGF16 mediates the GATA4 mutation in CHD. The GATA4 is an atrial septal defect hereditary mutatio","journal":"Cardiovascular Research","year":2021,"id":219816,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":12998,"name":"Joseph C. Wu","orcid":"0000-0002-6068-8041","position":1,"is_corresponding":false},{"id":819519,"name":"McKay M S Mullen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":12,"raw_metadata":null,"created_at":"2026-07-18T23:53:42.928212Z","pmid":"34971365","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}