{"doi":"10.1016/j.stemcr.2022.07.003","title":"Dual inhibition of MAPK and PI3K/AKT pathways enhances maturation of human iPSC-derived cardiomyocytes","abstract":"Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide great opportunities for mechanistic dissection of human cardiac pathophysiology; however, hiPSC-CMs remain immature relative to the adult heart. To identify novel signaling pathways driving the maturation process during heart development, we analyzed published transcriptional and epigenetic datasets from hiPSC-CMs and prenatal and postnatal human hearts. These analyses revealed that several components of the MAPK and PI3K-AKT pathways are downregulated in the postnatal heart. Here, we show that dual inhibition of these pathways for only 5 days significantly enhances the maturation of day 30 hiPSC-CMs in many domains: hypertrophy, multinucleation, metabolism, T-tubule density, calcium handling, and electrophysiology, many equivalent to day 60 hiPSC-CMs. These data indicate that the MAPK/PI3K/AKT pathways are involved in cardiomyocyte maturation and provide proof of concept for the manipulation of key signaling pathways for optimal hiPSC-CM maturation, a critical aspect of faithful in vitro modeling of cardiac pathologies and subsequent drug discovery.","journal":"Stem Cell Reports","year":2022,"id":241832,"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":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9347,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":732990,"name":"Sophie Givens","orcid":null,"position":1,"is_corresponding":false},{"id":871362,"name":"Phablo Abreu","orcid":"0000-0002-4143-6949","position":2,"is_corresponding":false},{"id":32545,"name":"Man Liu","orcid":"0000-0002-1390-7862","position":3,"is_corresponding":false},{"id":430363,"name":"Doğacan Yücel","orcid":"0009-0005-0471-7388","position":4,"is_corresponding":false},{"id":529282,"name":"June Baik","orcid":null,"position":5,"is_corresponding":false},{"id":871363,"name":"Noah Stanis","orcid":"0009-0000-0091-1056","position":6,"is_corresponding":false},{"id":872033,"name":"Taylor Rothermel","orcid":null,"position":7,"is_corresponding":false},{"id":366156,"name":"Alessandro Magli","orcid":"0000-0003-3874-2838","position":8,"is_corresponding":false},{"id":288568,"name":"Juan E. Abrahante","orcid":"0000-0002-9074-4307","position":9,"is_corresponding":false},{"id":871364,"name":"Natalya A. Goloviznina","orcid":"0000-0001-6002-4125","position":10,"is_corresponding":false},{"id":871365,"name":"Hossam A. N. Soliman","orcid":"0000-0002-9466-0012","position":11,"is_corresponding":false},{"id":712339,"name":"Neha R. Dhoke","orcid":null,"position":12,"is_corresponding":false},{"id":490515,"name":"Michael Kyba","orcid":"0000-0002-5579-7534","position":13,"is_corresponding":false},{"id":706772,"name":"Patrick W. Alford","orcid":"0000-0002-7811-4134","position":14,"is_corresponding":false},{"id":250665,"name":"Samuel C. Dudley","orcid":"0000-0001-5843-5961","position":15,"is_corresponding":false},{"id":334329,"name":"Jop H. van Berlo","orcid":"0000-0001-9229-4429","position":16,"is_corresponding":false},{"id":732190,"name":"Brenda M. Ogle","orcid":"0000-0001-7613-7490","position":17,"is_corresponding":false},{"id":872034,"name":"Rita Perlingeiro","orcid":null,"position":18,"is_corresponding":false},{"id":250327,"name":"Bayardo I. Garay","orcid":"0000-0002-1458-6095","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T00:23:00.865267Z","pmid":"35931076","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":[]}