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Krane, M.* ; Dreßen, M.* ; Santamaria, G.* ; My, I.* ; Schneider, C.M.* ; Dorn, T.* ; Laue, S.* ; Mastantuono, E. ; Berutti, R. ; Rawat, H.* ; Gilsbach, R.* ; Schneider, P.* ; Lahm, H.* ; Schwarz, S.* ; Doppler, S.A.* ; Paige, S.* ; Puluca, N.* ; Doll, S.* ; Neb, I.* ; Brade, T.* ; Zhang, Z.* ; Abou-Ajram, C.* ; Northoff, B.* ; Holdt, L.M.* ; Sudhop, S.* ; Sahara, M.* ; Goedel, A.* ; Dendorfer, A.* ; Tjong, F.V.Y.* ; Rijlaarsdam, M.E.* ; Cleuziou, J.* ; Lang, N.* ; Kupatt, C.* ; Bezzina, C.R.* ; Lange, R.* ; Bowles, N.E.* ; Mann, M.* ; Gelb, B.D.* ; Crotti, L.* ; Hein, L.* ; Meitinger, T. ; Wu, S.* ; Sinnecker, D.* ; Gruber, P.J.* ; Laugwitz, K.L.* ; Moretti, A.*

Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome.

Circulation 144, 1409-1428 (2021)
Publ. Version/Full Text DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. METHODS: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. RESULTS: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. CONCLUSIONS: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autophagy ; Cell Cycle ; Heart Defects, Congenital ; Hypoplastic Left Heart Syndrome ; Induced Pluripotent Stem Cells ; Unfolded Protein Response ; Whole Exome Sequencing; Unfolded Protein Response; Pluripotent Stem-cells; De-novo Variants; Cardiovascular Progenitors; Gene-expression; Fate Decisions; Outflow Tract; Smooth-muscle; Mutations; Transcription
ISSN (print) / ISBN 0009-7322
e-ISSN 1524-4539
Journal Circulation
Quellenangaben Volume: 144, Issue: 17, Pages: 1409-1428 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Two Commerce Sq, 2001 Market St, Philadelphia, Pa 19103 Usa
Reviewing status Peer reviewed
Grants Fondazione Umberto Veronesi
German Center for Cardiovascular Research
Transregio Research Unit
German Research Foundation
European Research Council