Extracellular vesicles derived from amniotic fluid stem cells as a novel strategy to prevent pulmonary hypertension secondary to congenital diaphragmatic hernia

• Applicant: Dr. Fabian Doktor
• Subject Area: General and Visceral Surgery ; Pediatric and Adolescent Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466815475

Congenital diaphragmatic hernia (CDH) is a birth defect that is characterized by the herniation of abdominal organs into the thoracic cavity with associated lung hypoplasia. Fetal hypoplastic lungs secondary to CDH show impaired growth, maturation and vascularization. Altered vascularization leads to postnatal pulmonary hypertension and high mortality. Since all CDH lung abnormalities start to take place in utero, the prenatal period is a window of opportunity to foster normal lung development. However, no antenatal therapy exists to fully rescue those lungs. In search for such a therapy, extracellular vesicles (EV) derived from amniotic fluid stem cells (AFSC) show great potential in experimental models of CDH, as they rescue lung growth and maturation. Preliminary data obtained in an experimental rat model show, that antenatal AFSC-EV administration can also recue vascular remodelling. By studying the cellular mechanisms that are involved in rat CDH with single-nucleus (sn)-RNA sequencing, we discovered that fetal CDH lungs are enriched with macrophages, AFSC-EVs attenuate the macrophage density and that the immune response may explain the lung impairments. This paradigm shift necessitates a modification in our experimental model to explain, how AFSC-EVs rescue vascularization. To overcome the limitations of the rat model, namely to perform lineage tracing and knock-out studies, we’ll use a mouse model of CDH, that is already established in the Zani lab. The first aim of the proposed experiments is to elucidate the role of macrophages in the pathogenesis of pulmonary hypoplasia and vascular remodelling secondary to CDH.

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