Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2022.878311/full |
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| author | Vittoria Marini Fabiola Marino Fabiola Marino Flaminia Aliberti Flaminia Aliberti Nefele Giarratana Enrico Pozzo Robin Duelen Álvaro Cortés Calabuig Rita La Rovere Tim Vervliet Daniele Torella Geert Bultynck Maurilio Sampaolesi Maurilio Sampaolesi Yoke Chin Chai |
| author_facet | Vittoria Marini Fabiola Marino Fabiola Marino Flaminia Aliberti Flaminia Aliberti Nefele Giarratana Enrico Pozzo Robin Duelen Álvaro Cortés Calabuig Rita La Rovere Tim Vervliet Daniele Torella Geert Bultynck Maurilio Sampaolesi Maurilio Sampaolesi Yoke Chin Chai |
| author_sort | Vittoria Marini |
| collection | DOAJ |
| description | Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-COs lack initial proliferative capacity, displayed a progressive loss of sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, cardiomyocyte deterioration, fibrosis and aberrant adipogenesis were observed in DMD-COs over time. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-COs which was associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies. |
| first_indexed | 2024-04-12T06:53:11Z |
| format | Article |
| id | doaj.art-e1250935e81c483f8fd7d6f1e6ccda3f |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-04-12T06:53:11Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-e1250935e81c483f8fd7d6f1e6ccda3f2022-12-22T03:43:16ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-08-011010.3389/fcell.2022.878311878311Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progressionVittoria Marini0Fabiola Marino1Fabiola Marino2Flaminia Aliberti3Flaminia Aliberti4Nefele Giarratana5Enrico Pozzo6Robin Duelen7Álvaro Cortés Calabuig8Rita La Rovere9Tim Vervliet10Daniele Torella11Geert Bultynck12Maurilio Sampaolesi13Maurilio Sampaolesi14Yoke Chin Chai15Translational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumDepartment of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, ItalyTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumFondazione IRCCS Policlinico San Matteo, Center for Inherited Cardiovascular Diseases, Transplant Research Area, Human Anatomy Unit, Department of Public Health, Experimental and Forensic Medicine, University of Pavia, Pavia, ItalyTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumGenomics Core Leuven, KU Leuven, Leuven, BelgiumLaboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Institute, KU Leuven, Leuven, BelgiumLaboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Institute, KU Leuven, Leuven, BelgiumDepartment of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, ItalyLaboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine and Leuven Kanker Institute, KU Leuven, Leuven, BelgiumTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumHistology and Medical Embryology Unit, Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, ItalyTranslational Cardiomyology Laboratory, Stem Cell Biology and Embryology, Department of Development and Regeneration, KU Leuven, Leuven, BelgiumDuchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disease which to date is incurable. The major cause of death is dilated cardiomyopathy however, its pathogenesis is unclear as existing cellular and animal models do not fully recapitulate the human disease phenotypes. In this study, we generated cardiac organoids from patient-derived induced pluripotent stem cells (DMD-COs) and isogenic-corrected controls (DMD-Iso-COs) and studied if DMD-related cardiomyopathy and disease progression occur in the organoids upon long-term culture (up to 93 days). Histological analysis showed that DMD-COs lack initial proliferative capacity, displayed a progressive loss of sarcoglycan localization and high stress in endoplasmic reticulum. Additionally, cardiomyocyte deterioration, fibrosis and aberrant adipogenesis were observed in DMD-COs over time. RNA sequencing analysis confirmed a distinct transcriptomic profile in DMD-COs which was associated with functional enrichment in hypertrophy/dilated cardiomyopathy, arrhythmia, adipogenesis and fibrosis pathways. Moreover, five miRNAs were identified to be crucial in this dysregulated gene network. In conclusion, we generated patient-derived cardiac organoid model that displayed DMD-related cardiomyopathy and disease progression phenotypes in long-term culture. We envision the feasibility to develop a more complex, realistic and reliable in vitro 3D human cardiac-mimics to study DMD-related cardiomyopathies.https://www.frontiersin.org/articles/10.3389/fcell.2022.878311/fullDuchenne muscular dystrophyinduced pluripotent stem cellscardiomyopathycardiac organoidsdisease modelingaberrant adipogenesis |
| spellingShingle | Vittoria Marini Fabiola Marino Fabiola Marino Flaminia Aliberti Flaminia Aliberti Nefele Giarratana Enrico Pozzo Robin Duelen Álvaro Cortés Calabuig Rita La Rovere Tim Vervliet Daniele Torella Geert Bultynck Maurilio Sampaolesi Maurilio Sampaolesi Yoke Chin Chai Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression Frontiers in Cell and Developmental Biology Duchenne muscular dystrophy induced pluripotent stem cells cardiomyopathy cardiac organoids disease modeling aberrant adipogenesis |
| title | Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression |
| title_full | Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression |
| title_fullStr | Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression |
| title_full_unstemmed | Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression |
| title_short | Long-term culture of patient-derived cardiac organoids recapitulated Duchenne muscular dystrophy cardiomyopathy and disease progression |
| title_sort | long term culture of patient derived cardiac organoids recapitulated duchenne muscular dystrophy cardiomyopathy and disease progression |
| topic | Duchenne muscular dystrophy induced pluripotent stem cells cardiomyopathy cardiac organoids disease modeling aberrant adipogenesis |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2022.878311/full |
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