title: Fetal reprogramming and senescence in hypoplastic left heart syndrome and in human pluripotent stem cells during cardiac differentiation.
abstract: Hypoplastic left heart syndrome (HLHS) is a severe cardiac malformation characterized by left ventricle (LV) hypoplasia and abnormal LV perfusion and oxygenation. We studied hypoxia-associated injury in fetal HLHS and human pluripotent stem cells during cardiac differentiation to assess the effect of microenvironmental perturbations on fetal cardiac reprogramming. We studied LV myocardial samples from 32 HLHS and 17 structurally normal midgestation fetuses. Compared with controls, the LV in fetal HLHS samples had higher nuclear expression of hypoxia-inducible factor-1α but lower angiogenic growth factor expression, higher expression of oncogenes and transforming growth factor (TGF)-β1, more DNA damage and senescence with cell cycle arrest, fewer cardiac progenitors, myocytes and endothelial lineages, and increased myofibroblast population (P < 0.05 versus controls). Smooth muscle cells (SMCs) had less DNA damage compared with endothelial cells and myocytes. We recapitulated the fetal phenotype by subjecting human pluripotent stem cells to hypoxia during cardiac differentiation. DNA damage was prevented by treatment with a TGF-β1 inhibitor (P < 0.05 versus nonhypoxic cells). The hypoplastic LV in fetal HLHS samples demonstrates hypoxia-inducible factor-1α up-regulation, oncogene-associated cellular senescence, TGF-β1-associated fibrosis and impaired vasculogenesis. The phenotype is recapitulated by subjecting human pluripotent stem cells to hypoxia during cardiac differentiation and rescued by inhibition of TGF-β1. This finding suggests that hypoxia may reprogram the immature heart and affect differentiation and development.
authors.affiliation: Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Naila
authors.initials: N
authors.lastname: Gaber
authors.forename: Mark
authors.initials: M
authors.lastname: Gagliardi
authors.forename: Pranali
authors.initials: P
authors.lastname: Patel
authors.forename: Caroline
authors.initials: C
authors.lastname: Kinnear
authors.forename: Cindy
authors.initials: C
authors.lastname: Zhang
authors.forename: David
authors.initials: D
authors.lastname: Chitayat
authors.forename: Patrick
authors.initials: P
authors.lastname: Shannon
authors.forename: Edgar
authors.initials: E
authors.lastname: Jaeggi
authors.forename: Uri
authors.initials: U
authors.lastname: Tabori
authors.forename: Gordon
authors.initials: G
authors.lastname: Keller
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
mesh_terms: D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002461:Cell Line, Transformed; D019070:Cell Lineage / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D058732:Embryoid Bodies / Q000187:drug effects / Q000473:pathology; D005333:Fetus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006352:Heart Ventricles / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000196:embryology* / Q000473:pathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D009024:Morphogenesis / Q000187:drug effects; D009153:Mutagens / Q000633:toxicity; D009206:Myocardium / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009153:Mutagens; D016212:Transforming Growth Factor beta