Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies
Congenital diaphragmatic hernia (CDH) is a complex disorder whereby improper formation of the diaphragm allows herniation of the internal organs into the thoracic cavity, resulting in pulmonary hypoplasia among other complications. Although epithelial dysfunction is central to CDH pathology, relativ...
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2025-05-01
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| author | Ophelia Aubert Olivia M. Dinwoodie Richard Wagner Xingbin Ai |
| author_facet | Ophelia Aubert Olivia M. Dinwoodie Richard Wagner Xingbin Ai |
| author_sort | Ophelia Aubert |
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| description | Congenital diaphragmatic hernia (CDH) is a complex disorder whereby improper formation of the diaphragm allows herniation of the internal organs into the thoracic cavity, resulting in pulmonary hypoplasia among other complications. Although epithelial dysfunction is central to CDH pathology, relatively little attention has been paid to the underlying mechanisms orchestrating epithelial malfunction. Proinflammatory signaling downstream of impaired mechanotransduction due to in utero lung compression has been elucidated to drive epithelial cell phenotypes. This has been illustrated by a reduction in nuclear YAP and the upregulation of NF-kB in CDH models. In this review, we draw from recent findings using emerging technologies to examine epithelial cell mechanisms in CDH and discuss the role of compression as a central and, crucially, sufficient driver of CDH phenotypes. In recognition of the limitations of using genetic knockout models to recapitulate such a heterogenic and etiologically complicated disease, we discuss alternative models such as the established nitrofen rat model, air–liquid interface (ALI) cultures, organoids and ex vivo lung explants. Throughout, we acknowledge the importance of involving mechanical compression in the modeling of CDH in order to faithfully recapitulate the disease. Finally, we explore novel therapeutic strategies from stem cell and regenerative therapies to precision medicine and the importance of defining CDH endotypes in order to guide treatments. |
| format | Article |
| id | doaj-art-eb33134eb62e476ca186843636ff0ea2 |
| institution | OA Journals |
| issn | 2073-4409 |
| language | English |
| publishDate | 2025-05-01 |
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| series | Cells |
| spelling | doaj-art-eb33134eb62e476ca186843636ff0ea22025-08-20T01:56:17ZengMDPI AGCells2073-44092025-05-01141068710.3390/cells14100687Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging TherapiesOphelia Aubert0Olivia M. Dinwoodie1Richard Wagner2Xingbin Ai3Department of Pediatric Surgery, University Medical Center Mannheim, 68165 Mannheim, GermanyDivision of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USADepartment of Pediatric Surgery, University Hospital Leipzig, 04103 Leipzig, GermanyDivision of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USACongenital diaphragmatic hernia (CDH) is a complex disorder whereby improper formation of the diaphragm allows herniation of the internal organs into the thoracic cavity, resulting in pulmonary hypoplasia among other complications. Although epithelial dysfunction is central to CDH pathology, relatively little attention has been paid to the underlying mechanisms orchestrating epithelial malfunction. Proinflammatory signaling downstream of impaired mechanotransduction due to in utero lung compression has been elucidated to drive epithelial cell phenotypes. This has been illustrated by a reduction in nuclear YAP and the upregulation of NF-kB in CDH models. In this review, we draw from recent findings using emerging technologies to examine epithelial cell mechanisms in CDH and discuss the role of compression as a central and, crucially, sufficient driver of CDH phenotypes. In recognition of the limitations of using genetic knockout models to recapitulate such a heterogenic and etiologically complicated disease, we discuss alternative models such as the established nitrofen rat model, air–liquid interface (ALI) cultures, organoids and ex vivo lung explants. Throughout, we acknowledge the importance of involving mechanical compression in the modeling of CDH in order to faithfully recapitulate the disease. Finally, we explore novel therapeutic strategies from stem cell and regenerative therapies to precision medicine and the importance of defining CDH endotypes in order to guide treatments.https://www.mdpi.com/2073-4409/14/10/687congenital diaphragmatic hernialung compressionairway epitheliummechanotransductionYAPNFkB |
| spellingShingle | Ophelia Aubert Olivia M. Dinwoodie Richard Wagner Xingbin Ai Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies Cells congenital diaphragmatic hernia lung compression airway epithelium mechanotransduction YAP NFkB |
| title | Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies |
| title_full | Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies |
| title_fullStr | Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies |
| title_full_unstemmed | Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies |
| title_short | Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies |
| title_sort | epithelial dysfunction in congenital diaphragmatic hernia mechanisms models and emerging therapies |
| topic | congenital diaphragmatic hernia lung compression airway epithelium mechanotransduction YAP NFkB |
| url | https://www.mdpi.com/2073-4409/14/10/687 |
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