{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:15Z","timestamp":1791316935009,"version":"4.3.1"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used\n                      <jats:italic toggle=\"yes\">Tbx18<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">Cre\/+<\/jats:italic>\n                      <\/jats:sup>\n                      and inducible\n                      <jats:italic toggle=\"yes\">WT1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">CreERT2\/+<\/jats:italic>\n                      <\/jats:sup>\n                      to generate epicardium-specific\n                      <jats:italic toggle=\"yes\">Numb<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">Numblike<\/jats:italic>\n                      double knockouts (epicardial\n                      <jats:italic toggle=\"yes\">Nb;Nl<\/jats:italic>\n                      double knockout [EDKO]) and inducible EpiC-specific\n                      <jats:italic toggle=\"yes\">Nb;Nl<\/jats:italic>\n                      knockout, respectively; monitored EpiCs\/EPDCs invasion into the myocardium by lineage tracing; assessed LVNC defects via the ratio of noncompact to compact zone thickness\/area; utilized single-nuclei mRNA sequencing and biochemical tools to determine the disrupted molecular mechanisms of EDKOs; and used pharmacological approaches to rescue defects in EDKOs. Cardiac structural and functional changes in adult stages were examined using echocardiography and histochemistry. Sample sizes ranged from 3 to 9 hearts across experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific\n                      <jats:italic toggle=\"yes\">Nb;Nl<\/jats:italic>\n                      knockouts (induced at embryonic day 10.5) recapitulated the defects. Single-nuclei mRNA sequencing revealed the upregulation of\n                      <jats:italic toggle=\"yes\">Fgfr1<\/jats:italic>\n                      (fibroblast growth factor receptor 1) in epicardium and the downregulation of\n                      <jats:italic toggle=\"yes\">Fgf<\/jats:italic>\n                      (fibroblast growth factor) ligands in cardiomyocytes in EDKOs. Exogenous Fgf2 supplementation to pregnant females partially rescued epithelial-mesenchymal transition and compaction defects in EDKO hearts. Female EDKOs survived to adulthood and maintained LVNC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Ablation of NFPs (Numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs\u2013Fgf\/Fgfr axis in regulating ventricular compaction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circheartfailure.125.013210","type":"journal-article","created":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T10:00:31Z","timestamp":1767261631000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Invasion of Epicardial-Derived Cells to the Trabeculae Mediated by NFPs-Fgf Signaling Regulates Ventricular Compaction"],"prefix":"10.1161","volume":"19","author":[{"given":"Anika","family":"Nusrat","sequence":"first","affiliation":[{"name":"Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy (A.N., L.Z., L.M., M.A.H., M.W.), University of Houston, 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