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.

One of the biggest challenges for babies with CDH is that fetal hypoplastic lungs are immature with impairment of cell differentiation, especially in the epithelium.

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

In a recently published proof of concept study, amniotic fluid stem cell derived EVs can rescue fetal lung growth and maturation in several models of CDH at the pseudoglandular stage, which corresponds to 7 to 16 weeks of human gestation.

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

The canalicular and saccular stages are translationally relevant developmental stages for CDH intervention, corresponding to the time when diagnosis occurs.

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 downregulation of alveolar type 1 and 2 cells, as well as basal and club cells compared to control lungs.

Treatment of hypoplastic lungs with amniotic fluid stem cell derived extracellular vesicles restores primary epithelial cell markers, indicating that cell homeostasis can be achieved.

We know halfway during pregnancy that babies with CDH are going to be born with abnormal lung development, creating an opportunity for prenatal interventions.

In vivo experiments using intraamniotic and tracheal administration routes of extracellular vesicles in rat models have shown promising results.

Safety and feasibility studies of AFSC-EV treatment are being investigated in collaboration with Jan Deprest in a lamb model.

Ciliated cells in hypoplastic CDH lungs did not show rescue with AFSC-EV treatment, which may reflect achievement of a different homeostatic cell composition rather than failure of the therapy.

Key markers of branching morphogenesis are being rescued effectively by AFSC-EV treatment.