Neurodevelopmental impairment in children with congenital diaphragmatic hernia: Not an uncommon complication for survivors

Montalva, Louise; Raffler, Gabriele; Riccio, Angela; Lauriti, Giuseppe; Zani, Augusto

doi:10.1016/j.jpedsurg.2019.05.021

Cited by 47 publications

(35 citation statements)

References 91 publications

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“…Based on previous studies and confirmed in this study, we established that 4x10 6 AFSCs cultured under these conditions secrete approximately 3x10 9 ± 1x10 7 EVs, as quantified by nanoparticle tracking analysis (29). For all in vitro, ex vivo, and in vivo experiments herein described, we administered 50 µL of the EV preparation that corresponds to 0.5% of the conditioned medium (50 µL EV volume of 10 mL CM volume, v/v) and 1.5x10 8 ± 5x10 5 EVs.…”

Section: Extracellular Vesicles (Evs)mentioning

confidence: 99%

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

et al. 2021

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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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Section: Extracellular Vesicles (Evs)mentioning

confidence: 99%

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

et al. 2021

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“…CDH can be life-threatening with overall 1-year survival of approximately 75% (Long et al, 2019). Neurodevelopmental impairment occurs in approximately 23% (Montalva et al, 2020). CDH has been estimated to occur in combination with other structural congenital anomalies in between 28% and 39% of cases (McGivern et al, 2015;Skari et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Beecroft

Ayala²,

McGillivray

et al. 2021

Human Mutation

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This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype Sarah J. Beecroft and Marcos Ayala joint first authors.

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“…50 Finally, a recent report uncovered that neurodevelopmental impairment is a relevant problem affecting one in four CDH survivors. 51 The authors identified ECMO demand, severe pulmonary hypoplasia, and large defect size as the main risk factors. It will be crucial in future studies to determine whether thoracoscopy or open surgery can be associated with an additional increase in neurodevelopmental disorders in CDH patients.…”

Section: Thoracoscopic Repair and Ecmomentioning

confidence: 99%

Thoracoscopic Repair of Congenital Diaphragmatic Hernia

Wagner

Mayer

et al. 2020

Eur J Pediatr Surg

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The surgical management of patients with congenital diaphragmatic hernia (CDH) is challenging and ever changing. It requires the highest expertise not only on the surgical level but also of neonatologists and anesthesiologists. In selected patients traditional open surgery is increasingly replaced by thoracoscopic CDH repair in many centers worldwide. Despite obvious and well-described advantages of the minimally invasive approach like a shorter ventilatory time, less pain, a shorter hospital length of stay, and a better cosmesis, important controversies remain. This review discusses hot topics of minimally invasive CDH repair, such as extracorporeal membrane oxygenation, hypercapnia/acidosis, patch repair, surgical training, and recurrence.

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Neurodevelopmental impairment in children with congenital diaphragmatic hernia: Not an uncommon complication for survivors

Cited by 47 publications

References 91 publications

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

Fetal lung underdevelopment is rescued by administration of amniotic fluid stem cell extracellular vesicles in rodents

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects

Thoracoscopic Repair of Congenital Diaphragmatic Hernia

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