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


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.

SUBMITTER: Krane M 

PROVIDER: S-EPMC8542085 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Krane Markus M   Dreßen Martina M   Santamaria Gianluca G   My Ilaria I   Schneider Christine M CM   Dorn Tatjana T   Laue Svenja S   Mastantuono Elisa E   Berutti Riccardo R   Rawat Hilansi H   Gilsbach Ralf R   Schneider Pedro P   Lahm Harald H   Schwarz Sascha S   Doppler Stefanie A SA   Paige Sharon S   Puluca Nazan N   Doll Sophia S   Neb Irina I   Brade Thomas T   Zhang Zhong Z   Abou-Ajram Claudia C   Northoff Bernd B   Holdt Lesca M LM   Sudhop Stefanie S   Sahara Makoto M   Goedel Alexander A   Dendorfer Andreas A   Tjong Fleur V Y FVY   Rijlaarsdam Maria E ME   Cleuziou Julie J   Lang Nora N   Kupatt Christian C   Bezzina Connie C   Lange Rüdiger R   Bowles Neil E NE   Mann Matthias M   Gelb Bruce D BD   Crotti Lia L   Hein Lutz L   Meitinger Thomas T   Wu Sean S   Sinnecker Daniel D   Gruber Peter J PJ   Laugwitz Karl-Ludwig KL   Moretti Alessandra A  

Circulation 20211025 17


<h4>Background</h4>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.<h4>Methods</h4>To identify perturbations in gene programs controlling ventricular  ...[more]

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