{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T16:01:03Z","timestamp":1793548863348,"version":"4.5.0"},"reference-count":82,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,1,20]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              <jats:italic>NOTCH1<\/jats:italic>\n              pathogenic variants are implicated in multiple types of congenital heart defects including hypoplastic left heart syndrome, where the left ventricle is underdeveloped. It is unknown how\n              <jats:italic>NOTCH1<\/jats:italic>\n              regulates human cardiac cell lineage determination and cardiomyocyte proliferation. In addition, mechanisms by which\n              <jats:italic>NOTCH1<\/jats:italic>\n              pathogenic variants lead to ventricular hypoplasia in hypoplastic left heart syndrome remain elusive.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)\/Cas9 genome editing was utilized to delete\n              <jats:italic>NOTCH1<\/jats:italic>\n              in human induced pluripotent stem cells. Cardiac differentiation was carried out by sequential modulation of WNT signaling, and\n              <jats:italic>NOTCH1<\/jats:italic>\n              knockout and wild-type differentiating cells were collected at day 0, 2, 5, 10, 14, and 30 for single-cell RNA-seq.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Human\n              <jats:italic>NOTCH1<\/jats:italic>\n              knockout induced pluripotent stem cells are able to generate functional cardiomyocytes and endothelial cells, suggesting that NOTCH1 is not required for mesoderm differentiation and cardiovascular development in vitro. However, disruption of NOTCH1 blocks human ventricular-like cardiomyocyte differentiation but promotes atrial-like cardiomyocyte generation through shortening the action potential duration.\n              <jats:italic>NOTCH1<\/jats:italic>\n              deficiency leads to defective proliferation of early human cardiomyocytes, and transcriptomic analysis indicates that pathways involved in cell cycle progression and mitosis are downregulated in\n              <jats:italic>NOTCH1<\/jats:italic>\n              knockout cardiomyocytes. Single-cell transcriptomic analysis reveals abnormal cell lineage determination of cardiac mesoderm, which is manifested by the biased differentiation toward epicardial and second heart field progenitors at the expense of first heart field progenitors in\n              <jats:italic>NOTCH1<\/jats:italic>\n              knockout cell populations.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              <jats:italic>NOTCH1<\/jats:italic>\n              is essential for human ventricular-like cardiomyocyte differentiation and proliferation through balancing cell fate determination of cardiac mesoderm and modulating cell cycle progression. Because first heart field progenitors primarily contribute to the left ventricle, we speculate that pathogenic\n              <jats:italic>NOTCH1<\/jats:italic>\n              variants lead to biased differentiation of first heart field progenitors, blocked ventricular-like cardiomyocyte differentiation, and defective cardiomyocyte proliferation, which collaboratively contribute to left ventricular hypoplasia in hypoplastic left heart syndrome.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.122.321398","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T10:01:05Z","timestamp":1672394465000},"page":"187-204","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":60,"title":["Impaired Human Cardiac Cell Development due to NOTCH1 Deficiency"],"prefix":"10.1161","volume":"132","author":[{"given":"Shiqiao","family":"Ye","sequence":"first","affiliation":[{"name":"Center for 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