{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T15:00:23Z","timestamp":1787238023435,"version":"build-2736575974"},"reference-count":96,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R03HD113887"],"award-info":[{"award-number":["R03HD113887"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013liquid 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.<\/jats:p>","DOI":"10.3390\/cells14100687","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T11:25:53Z","timestamp":1746789953000},"page":"687","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Epithelial Dysfunction in Congenital Diaphragmatic Hernia: Mechanisms, Models and Emerging Therapies"],"prefix":"10.3390","volume":"14","author":[{"given":"Ophelia","family":"Aubert","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, University Medical Center Mannheim, 68165 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia M.","family":"Dinwoodie","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3035-2619","authenticated-orcid":false,"given":"Richard","family":"Wagner","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, University Hospital Leipzig, 04103 Leipzig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingbin","family":"Ai","sequence":"additional","affiliation":[{"name":"Division of Newborn Medicine, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eabc3172","DOI":"10.1126\/science.abc3172","article-title":"Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus","volume":"371","author":"Zepp","year":"2021","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/s41580-019-0141-3","article-title":"Cellular crosstalk in the development and regeneration of the respiratory system","volume":"20","author":"Zepp","year":"2019","journal-title":"Nat. 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