Targeting Endothelial-to-Mesenchymal Transition in Fetal Lung Vascular Remodeling: A New Strategy for Congenital Diaphragmatic Hernia Lungs

• Applicant: Dr. Lucas Wennemann
• Subject Area: General and Visceral Surgery ; Pediatric and Adolescent Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574598469

Congenital diaphragmatic hernia (CDH) is a rare birth defect affecting approximately 2.3 per 10,000 live births worldwide. It occurs when abdominal organs herniate into the chest during fetal development, restricting normal lung growth. This results in pulmonary hypoplasia, a condition characterized by impaired growth, maturation, and vascularization in both fetal lungs. The latter results from pulmonary vascular remodeling in utero, which leads postnatally to pulmonary hypertension (CDH-PH) in about 90% of neonates. The main cause of morbidity and mortality is the severity of pulmonary hypoplasia and pulmonary vascular remodeling leading to CDH-PH. Despite advances in pre- and postnatal care, overall morbidity and mortality in CDH have not significantly improved in recent years. CDH causes prenatal or postnatal death in approximately 50% of cases, with mortality rates reaching up to 99% in low-income countries. Two-thirds of CDH survivors experience lifelong pulmonary complications that significantly impact their quality of life. Since hypoplastic lungs are the root cause of both mortality and morbidity in CDH, restoring normal lung development remains the primary focus of any therapeutic strategy. However, while the diaphragm can be surgically repaired postnatally, no treatment to date fully rescues lung development. This challenge is further aggravated by the persistent underfunding of research into pediatric and rare diseases, particularly in pediatric surgery. Recent work from Dr. Augusto Zani’s laboratory has introduced a promising regenerative medicine approach utilizing extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs). In preclinical models, AFSC-EVs have demonstrated the ability to rescue impaired lung development by promoting lung growth, maturation, and vascularization, as well as reducing inflammation. Importantly, the lab recently identified dysregulated endothelial-to-mesenchymal transition (EndMT) as a key mechanism underlying CDH-PH, a process that disrupts normal vascular development. In CDH animal models, AFSC-EV treatment reduced pathological EndMT and restored normal vascular features. However, the precise mechanisms by which AFSC-EVs influence vascular remodeling remain unknown. This project aims to investigate the role of EndMT in CDH-associated vascular remodeling and how antenatal AFSC-EV treatment may reverse it. By targeting this pathological mechanism during fetal life, we seek to restore normal lung vascular development and reduce the risk of postnatal CDH-PH. Our goal is to develop a novel antenatal, regenerative medicine-based therapy for CDH. This project offers a translational approach to rescuing lung development as the most critical aspect of CDH in order to improve overall survival, reduce long-term complications, and ultimately help affected children achieve a better quality of life.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Augusto Zani, Ph.D.