PhD Student University of Rome Tor Vergata, Lazio, Italy
Abstract: Congenital Diaphragmatic Hernia (CDH) is a congenital malformation characterized by an incomplete diaphragm closure, with subsequent herniation of abdominal organs into the chest cavity. This causes a mechanical compression exerted on the fetal airways, that results in an underdevelopment of fetal lungs and pulmonary vasculature with consequent hypertension. Fetuses with severe CDH undergo FETO, an in utero procedure where an inflatable balloon is inserted into the fetal trachea, causing the retention of lung secretions in order to ameliorate lung hypoplasia. Despite advances in prenatal diagnosis and management of CDH cases, predicting disease severity, response to treatment and patients’ clinical outcomes remains a challenge, therefore limiting parental counselling. More reliable predictive parameters are therefore needed to obtain personalized modeling and improve CDH outcomes. In this context, primary organoids are able to recapitulate in vitro some pathophysiological features of patients’ tissues, allowing for disease modelling and drug screening. Relevantly, our group has recently identified in the amniotic fluid (AF) epithelial precursors able to originate AF-derived organoids (AFO) resembling different fetal organs (kidney, lung and intestine). AFO have the potential to model fetal diseased organs without the ethical and legal limitations of accessing fetal tissues. In this project we derived fetal lung organoids from 41 CDH AF, collected during scheduled amniocentesis and FETO procedures. Our data suggests that, when derived from CDH samples, lung AFO reflect in vitro some features of the disease. In detail scRNA sequencing analysis reveals altered cellular composition in CDH lung AFO, when compared to age-matched controls. Likewise, upon differentiation, we observed alterations in surfactant production and ciliation. These differences align to what has been observed in CDH animal models and human tissue specimens. In conclusion, the use of lung AFO would allow disease modelling in a patient-specific manner and help underpin the molecular mechanism underlying lung hypoplasia in CDH patients.
Funding Source: This work was supported by the Academy of Medical Science, UCL Therapeutic Acceleration Support, GOSH-CC, Kidney Research UK, CDH-UK, NIHR GOSH BRC and Rosetrees Trust. GD is supported by an EMBO Scientific Exchange Grant.
