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

Krane M, Dressen M, Santamaria G, My I, Schneider CM, Dorn T, Laue S, Mastantuono E, Berutti R, Rawat H, Gilsbach R, Schneider P, Lahm H, Schwarz S, Doppler SA, Paige S, Puluca N, Doll S, Neb I, Brade T, Zhang Z, Abou-Ajram C, Northoff B, Holdt LM, Sudhop S, Sahara M, Goedel A, Dendorfer A, Tjong FVY, Rijlaarsdam ME, Cleuziou J, Lang N, Kupatt C, Bezzina C, Lange R, Bowles NE, Mann M, Gelb BD, Crotti L, Hein L, Meitinger T, Wu S, Sinnecker D, Gruber PJ, Laugwitz KL, Moretti A (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Pages Range: 1409-1428

DOI: 10.1161/CIRCULATIONAHA.121.056198

Abstract

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.

Involved external institutions

Technische Universität München (TUM) Germany (DE) Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK e.V.) Germany (DE) University of Amsterdam Netherlands (NL) Leiden University Netherlands (NL) University of Utah United States (USA) (US) Stanford University United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) Albert-Ludwigs-Universität Freiburg Germany (DE) Yale University United States (USA) (US) Hochschule für angewandte Wissenschaften München Germany (DE) Max-Planck-Institut für Biochemie / Max Planck Institute of Biochemistry Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Karolinska Institute Sweden (SE)

How to cite

APA:

Krane, M., Dressen, M., Santamaria, G., My, I., Schneider, C.M., Dorn, T.,... Moretti, A. (2021). Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome. Circulation, 1409-1428. https://dx.doi.org/10.1161/CIRCULATIONAHA.121.056198

MLA:

Krane, Markus, et al. "Sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome." Circulation (2021): 1409-1428.

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