CAPS - Administration of amniotic fluid stem cell extracellular vesicles regenerates the lung epithelium in fetal rats with CDH at translationally relevant developmental stages - Kasra Khalaj

Congenital diaphragmatic hernia is characterized by impaired fetal lung growth and maturation with unacceptably high mortality and morbidity rates.

Fetal hypoplastic lungs in CDH are immature with impairment of cell differentiation, especially in the epithelium.

Extracellular vesicles (EVs) are the main mediators of stem cell paracrine signaling.

Amniotic fluid stem cell-derived EVs can rescue fetal lung growth and maturation in several models of CDH at the pseudoglandular stage (corresponding to 7-16 weeks of human gestation).

CDH is diagnosed around 18-20 weeks of human gestation.

The canalicular and saccular stages are translationally relevant developmental stages for CDH intervention, corresponding to when the condition can be diagnosed.

The nitrofen model is a well-established model for studying CDH, created by administering the herbicide nitrofen to pregnant rat dams at embryonic day 9.5.

Key epithelial populations in the fetal lung include alveolar type 1 and type 2 cells (primarily comprising the alveolus), and club, ciliated, and basal cells (mainly comprising the bronchi and bronchioles).

Hypoplastic lungs at canalicular and saccular stages show down-regulation of alveolar type 1 and 2 cells, as well as basal and club cells compared to control.

Treatment with amniotic fluid stem cell-derived extracellular vesicles restores primary markers of alveolar type 1 and 2 cells, basal cells, and club cells in hypoplastic lungs, indicating that cell homeostasis can be achieved.

There is an opportunity for prenatal interventions in CDH since the condition is diagnosed halfway through pregnancy, but currently clinicians wait until birth.

In vivo experiments have been performed using intraamniotic and tracheal administration routes for extracellular vesicles in a rat model, with promising results.

Safety and feasibility studies of AFSCEV treatment are being investigated in collaboration with Jan De Prest in a lamb model.

Ciliated cells were not rescued by AFSCEV treatment, which may reflect achievement of a different homeostatic cell composition rather than failure of the treatment.

Key markers of branching morphogenesis are being effectively rescued by AFSCEV treatment.