RESUMEN

Fetal lung underdevelopment, also known as pulmonary hypoplasia, is characterized by decreased lung growth and maturation. The most common birth defect found in babies with pulmonary hypoplasia is congenital diaphragmatic hernia (CDH). Despite research and clinical advances, babies with CDH still have high morbidity and mortality rates, which are directly related to the severity of lung underdevelopment. To date, there is no effective treatment that promotes fetal lung growth and maturation. Here, we describe a stem cell-based approach in rodents that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). Using fetal rodent models of pulmonary hypoplasia (primary epithelial cells, organoids, explants, and in vivo), we demonstrated that AFSC-EV administration promoted branching morphogenesis and alveolarization, rescued tissue homeostasis, and stimulated epithelial cell and fibroblast differentiation. We confirmed this regenerative ability in in vitro models of lung injury using human material, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. Investigating EV mechanism of action, we found that AFSC-EV beneficial effects were exerted via the release of RNA cargo. MicroRNAs regulating the expression of genes involved in lung development, such as the miR17-92 cluster and its paralogs, were highly enriched in AFSC-EVs and were increased in AFSC-EV-treated primary lung epithelial cells compared to untreated cells. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application in patients with pulmonary hypoplasia.

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RESUMEN

Despite advances in intensive care, several neonatal conditions typically due to prematurity affect vital organs and are associated with high mortality and long-term morbidities. Current treatment strategies for these babies are only partially successful or are effective only in selected patients. Regenerative medicine has been shown to be a promising option for these conditions at an experimental level, but still warrants further exploration for the development of optimal treatment. Although stem cell-based therapy has emerged as a treatment option, studies have shown that it is associated with potential risks and hazards, especially in the fragile population of babies. Recently, extracellular vesicles (EVs) have emerged as an attractive therapeutic alternative that holds great regenerative potential and is cell-free. EVs are nanosized particles endogenously produced by cells that mediate intercellular communication through the transfer of their cargo. Currently, EVs are garnering considerable attention as they are the key effectors of stem cell paracrine signaling and can epigenetically regulate target cell genes through the release of RNA species, such as microRNA. Herein, we review the emerging literature on the therapeutic potential of EVs derived from different sources for the treatment of neonatal conditions that affect the brain, retinas, spine, lungs, and intestines and discuss the challenges for the translation of EVs into clinical practice.