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  Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome

Krane, M., Dressen, M., Santamaria, G., My, I., Schneider, C. M., Dorn, T., et al. (2021). Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome. Circulation, 144(17), 1409-1428. doi:10.1161/CIRCULATIONAHA.121.056198.

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CIRCULATIONAHA.121.056198.pdf (Publisher version), 8MB
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© 2021 The Authors.

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 Creators:
Krane, Markus1, Author
Dressen, Martina1, Author
Santamaria, Gianluca1, Author
My, Ilaria1, Author
Schneider, Christine M.1, Author
Dorn, Tatjana1, Author
Laue, Svenja1, Author
Mastantuono, Elisa1, Author
Berutti, Riccardo1, Author
Rawat, Hilansi1, Author
Gilsbach, Ralf1, Author
Schneider, Pedro1, Author
Lahm, Harald1, Author
Schwarz, Sascha1, Author
Doppler, Stefanie A.1, Author
Paige, Sharon1, Author
Puluca, Nazan1, Author
Doll, Sophia2, Author              
Neb, Irina1, Author
Brade, Thomas1, Author
Zhang, Zhong1, AuthorAbou-Ajram, Claudia1, AuthorNorthoff, Bernd1, AuthorHoldt, Lesca M.1, AuthorSudhop, Stefanie1, AuthorSahara, Makoto1, AuthorGoedel, Alexander1, AuthorDendorfer, Andreas1, AuthorTjong, Fleur V. Y.1, AuthorRijlaarsdam, Maria E.1, AuthorCleuziou, Julie1, AuthorLang, Nora1, AuthorKupatt, Christian1, AuthorBezzina, Connie1, AuthorLange, Rudiger1, AuthorBowles, Neil E.1, AuthorMann, Matthias1, AuthorGelb, Bruce D.1, AuthorCrotti, Lia1, AuthorHein, Lutz1, AuthorMeitinger, Thomas1, AuthorWu, Sean1, AuthorSinnecker, Daniel1, AuthorGruber, Peter J.1, AuthorLaugwitz, Karl-Ludwig1, AuthorMoretti, Alessandra1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: UNFOLDED PROTEIN RESPONSE; PLURIPOTENT STEM-CELLS; DE-NOVO VARIANTS; CARDIOVASCULAR PROGENITORS; GENE-EXPRESSION; FATE DECISIONS; OUTFLOW TRACT; SMOOTH-MUSCLE; MUTATIONS; TRANSCRIPTIONCardiovascular System & Cardiology; autophagy; cell cycle; heart defects; congenital; hypoplastic left heart syndrome; induced pluripotent stem cells; unfolded protein response; whole exome sequencing;
 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.

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Language(s): eng - English
 Dates: 2021
 Publication Status: Published in print
 Pages: 20
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Degree: -

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Title: Circulation
Source Genre: Journal
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Publ. Info: Dallas, Tex., etc. : American Heart Association, etc.
Pages: - Volume / Issue: 144 (17) Sequence Number: - Start / End Page: 1409 - 1428 Identifier: ISSN: 0009-7322
CoNE: https://pure.mpg.de/cone/journals/resource/954925390275