Fabian Doktor, Lina Antounians, Rebeca Lopes Figueira, Kasra Khalaj, Miriam Duci, Augusto Zani
Hospital for Sick Children and University of Toronto. Leipzig University.
Canada and Germany
Stem Cells Translational Medicine
Stem Cells Transl Med 2025; 14:
DOI: 10.1093/stcltm/szae095
Abstract
Disruption of developmental processes affecting the fetal lung leads to pulmonary hypoplasia. Pulmonary hypoplasia results from several conditions including congenital diaphragmatic hernia (CDH) and oligohydramnios. Both entities have high morbidity and mortality, and no effective therapy that fully restores normal lung development. Hypoplastic lungs have impaired growth (arrested branching morphogenesis), maturation (decreased epithelial/mesenchymal differentiation), and vascularization (endothelial dysfunction and vascular remodeling leading to postnatal pulmonary hypertension). Herein, we discuss the pathogenesis of pulmonary hypoplasia and the role of microRNAs (miRNAs) during normal and pathological lung development. Since multiple cells and pathways are altered, the ideal strategy for hypoplastic lungs is to deliver a therapy that addresses all aspects of abnormal lung development. In this review, we report on a novel regenerative approach based on the administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs). Specifically, we describe the effects of AFSC-EVs in rodent and human models of pulmonary hypoplasia, their mechanism of action via release of their cargo, including miRNAs, and their anti-inflammatory properties. We also compare cargo contents and regenerative effects of EVs from AFSCs and mesenchymal stromal cells (MSCs). Overall, there is compelling evidence that antenatal administration of AFSC-EVs rescues multiple features of fetal lung development in experimental models of pulmonary hypoplasia. Lastly, we discuss the steps that need to be taken to translate this promising EV-based therapy from the bench to the bedside. These include strategies to overcome barriers commonly associated with EV therapeutics and specific challenges related to stem cell-based therapies in fetal medicine.
Category
Class III. Pulmonary Hypertension Associated with Lung Hypoplasia
Medical Therapy. Efficacy or Lack of Efficacy
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Animal Models of Pulmonary Vascular Disease and Therapy
Review Articles Concerning Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes