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Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome
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 hypo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542085/ https://www.ncbi.nlm.nih.gov/pubmed/34694888 http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056198 |
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author | Krane, Markus Dreßen, Martina Santamaria, Gianluca My, Ilaria Schneider, Christine M. Dorn, Tatjana Laue, Svenja Mastantuono, Elisa Berutti, Riccardo Rawat, Hilansi Gilsbach, Ralf Schneider, Pedro Lahm, Harald Schwarz, Sascha Doppler, Stefanie A. Paige, Sharon Puluca, Nazan Doll, Sophia Neb, Irina Brade, Thomas Zhang, Zhong Abou-Ajram, Claudia Northoff, Bernd Holdt, Lesca M. Sudhop, Stefanie Sahara, Makoto Goedel, Alexander Dendorfer, Andreas Tjong, Fleur V.Y. Rijlaarsdam, Maria E. Cleuziou, Julie Lang, Nora Kupatt, Christian Bezzina, Connie Lange, Rüdiger Bowles, Neil E. Mann, Matthias Gelb, Bruce D. Crotti, Lia Hein, Lutz Meitinger, Thomas Wu, Sean Sinnecker, Daniel Gruber, Peter J. Laugwitz, Karl-Ludwig Moretti, Alessandra |
author_facet | Krane, Markus Dreßen, Martina Santamaria, Gianluca My, Ilaria Schneider, Christine M. Dorn, Tatjana Laue, Svenja Mastantuono, Elisa Berutti, Riccardo Rawat, Hilansi Gilsbach, Ralf Schneider, Pedro Lahm, Harald Schwarz, Sascha Doppler, Stefanie A. Paige, Sharon Puluca, Nazan Doll, Sophia Neb, Irina Brade, Thomas Zhang, Zhong Abou-Ajram, Claudia Northoff, Bernd Holdt, Lesca M. Sudhop, Stefanie Sahara, Makoto Goedel, Alexander Dendorfer, Andreas Tjong, Fleur V.Y. Rijlaarsdam, Maria E. Cleuziou, Julie Lang, Nora Kupatt, Christian Bezzina, Connie Lange, Rüdiger Bowles, Neil E. Mann, Matthias Gelb, Bruce D. Crotti, Lia Hein, Lutz Meitinger, Thomas Wu, Sean Sinnecker, Daniel Gruber, Peter J. Laugwitz, Karl-Ludwig Moretti, Alessandra |
author_sort | Krane, Markus |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8542085 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-85420852021-10-27 Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome Krane, Markus Dreßen, Martina Santamaria, Gianluca My, Ilaria Schneider, Christine M. Dorn, Tatjana Laue, Svenja Mastantuono, Elisa Berutti, Riccardo Rawat, Hilansi Gilsbach, Ralf Schneider, Pedro Lahm, Harald Schwarz, Sascha Doppler, Stefanie A. Paige, Sharon Puluca, Nazan Doll, Sophia Neb, Irina Brade, Thomas Zhang, Zhong Abou-Ajram, Claudia Northoff, Bernd Holdt, Lesca M. Sudhop, Stefanie Sahara, Makoto Goedel, Alexander Dendorfer, Andreas Tjong, Fleur V.Y. Rijlaarsdam, Maria E. Cleuziou, Julie Lang, Nora Kupatt, Christian Bezzina, Connie Lange, Rüdiger Bowles, Neil E. Mann, Matthias Gelb, Bruce D. Crotti, Lia Hein, Lutz Meitinger, Thomas Wu, Sean Sinnecker, Daniel Gruber, Peter J. Laugwitz, Karl-Ludwig Moretti, Alessandra Circulation Original Research Articles 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. Lippincott Williams & Wilkins 2021-10-26 2021-10-26 /pmc/articles/PMC8542085/ /pubmed/34694888 http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056198 Text en © 2021 The Authors. https://creativecommons.org/licenses/by-nc-nd/4.0/Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial-NoDerivs (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited, the use is noncommercial, and no modifications or adaptations are made. |
spellingShingle | Original Research Articles Krane, Markus Dreßen, Martina Santamaria, Gianluca My, Ilaria Schneider, Christine M. Dorn, Tatjana Laue, Svenja Mastantuono, Elisa Berutti, Riccardo Rawat, Hilansi Gilsbach, Ralf Schneider, Pedro Lahm, Harald Schwarz, Sascha Doppler, Stefanie A. Paige, Sharon Puluca, Nazan Doll, Sophia Neb, Irina Brade, Thomas Zhang, Zhong Abou-Ajram, Claudia Northoff, Bernd Holdt, Lesca M. Sudhop, Stefanie Sahara, Makoto Goedel, Alexander Dendorfer, Andreas Tjong, Fleur V.Y. Rijlaarsdam, Maria E. Cleuziou, Julie Lang, Nora Kupatt, Christian Bezzina, Connie Lange, Rüdiger Bowles, Neil E. Mann, Matthias Gelb, Bruce D. Crotti, Lia Hein, Lutz Meitinger, Thomas Wu, Sean Sinnecker, Daniel Gruber, Peter J. Laugwitz, Karl-Ludwig Moretti, Alessandra Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title | Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title_full | Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title_fullStr | Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title_full_unstemmed | Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title_short | Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome |
title_sort | sequential defects in cardiac lineage commitment and maturation cause hypoplastic left heart syndrome |
topic | Original Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542085/ https://www.ncbi.nlm.nih.gov/pubmed/34694888 http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056198 |
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