Endoplasmic reticulum stress response is activated in pulmonary hypoplasia secondary to congenital diaphragmatic hernia, but is decreased by administration of amniotic fluid stem cells

Tzanetakis, Areti; Antounians, Lina; Belfiore, Alyssa; Ma, Qiang; Stasiewicz, Mark; Pellerito, Ornella; Zani, Augusto

doi:10.1007/s00383-018-4376-4

Cited by 13 publications

(14 citation statements)

References 34 publications

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“…For primary cell studies, single cell suspensions of E14.5 and E17.5 lungs were enriched for epithelial cells using an established protocol (5,21,22).…”

Section: Experimental Models Of Pulmonary Hypoplasiamentioning

confidence: 99%

Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles

Khalaj

Antounians

Figueira

et al. 2022

Preprint

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Rationale: Pulmonary hypoplasia secondary to congenital diaphragmatic hernia (CDH) is characterized by reduced branching morphogenesis, which is responsible for poor clinical outcomes. Administration of amniotic fluid stem cell extracellular vesicles (AFSC-EVs) rescues branching morphogenesis in rodent fetal models of pulmonary hypoplasia. Herein, we hypothesized that AFSC-EVs exert their regenerative potential by affecting autophagy, a process required for normal lung development. Objectives: To evaluate autophagy in hypoplastic lungs throughout gestation and establish whether AFSC-EV administration improves branching morphogenesis through autophagy-mediated mechanisms. Methods: EVs were isolated from c-kit+ AFSC conditioned medium by ultracentrifugation and characterized for size, morphology, and EV markers. Branching morphogenesis was inhibited in rat fetuses by nitrofen administration to dams and in human fetal lung explants by blocking RAC1 activity with NSC23766. Expression of autophagy activators (BECN1 and ATG5) and adaptor (SQSTM1/p62) was analyzed in vitro (rat and human fetal lung explants) and in vivo (rat fetal lungs). Mechanistic studies on rat fetal primary lung epithelial cells were conducted using inhibitors for microRNA-17 and -20a contained in the AFSC-EV cargo and known to regulate autophagy. Measurements and Main Results: Rat and human models of fetal pulmonary hypoplasia showed reduced autophagy mainly at pseudoglandular and canalicular stages. AFSC-EV administration restored autophagy in both pulmonary hypoplasia models by transferring miR-17~92 cluster members contained in the EV cargo. Conclusions: AFSC-EV treatment rescues branching morphogenesis partly by restoring autophagy through miRNA cargo transfer. This study enhances our understanding of pulmonary hypoplasia pathogenesis and creates new opportunities for fetal therapeutic intervention in CDH babies.

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“…For primary cell studies, single cell suspensions of E14.5 and E17.5 lungs were enriched for epithelial cells using an established protocol (5,21,22).…”

Section: Experimental Models Of Pulmonary Hypoplasiamentioning

confidence: 99%

Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles

Khalaj

Antounians

Figueira

et al. 2022

Preprint

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“…A hallmark of pulmonary hypoplasia secondary to CDH is the impairment in the homeostasis of the respiratory epithelium (2,40). Administration of AFSC-EVs to primary lung epithelial cells isolated from hypoplastic lungs of nitrofen exposed fetuses increased proliferation and reduced cell death back to control levels (Fig.…”

Section: Afsc-ev Administration Restores Homeostasis and Stimulates Dmentioning

confidence: 99%

“…Ex vivo -In fetal rats, pulmonary hypoplasia was induced as previously described (30,40) with the administration of nitrofen to pregnant dams (100mg) by oral gavage on E 9.5. At E14.5, the dam was euthanized, and fetal lungs were micro-dissected.…”

Section: Experimental Models Of Pulmonary Hypoplasiamentioning

confidence: 99%

“…In vitro -1) For primary epithelial cell experiments in rats, a single cell suspension was obtained at E14.5 from pooled lungs from either control or nitrofen exposed rat fetuses by trypsinization for 20 minutes. Cells were subjected to three serial depletions of fibroblasts by incubation for 1h each following an established protocol (40,62). 2) For organoid studies, cells were seeded in a ratio of 60:40 semi-solid Matrigel to medium, as previously described (63).…”

Section: Experimental Models Of Pulmonary Hypoplasiamentioning

confidence: 99%

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Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

Antounians

Catania

Montalva

et al. 2020

Preprint

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Incomplete lung development, also known as pulmonary hypoplasia, is a recognized cause of neonatal death and poor outcome for survivors. To date, there is no effective treatment that promotes fetal lung growth and maturation. Herein, we describe a novel stem cell-based approach that enhances fetal lung development via the administration of extracellular vesicles (EVs) derived from amniotic fluid stem cells (AFSCs). In experimental models of pulmonary hypoplasia, administration of AFSC-EVs promoted lung branching morphogenesis and alveolarization, and stimulated pulmonary epithelial cell and fibroblast differentiation. This regenerative ability was confirmed in two models of injured human lung cells, where human AFSC-EVs obtained following good manufacturing practices restored pulmonary epithelial homeostasis. AFSC-EV beneficial effects were exerted via the release of RNA cargo, primarily miRNAs, that regulate the expression of genes involved in fetal lung development. Our findings suggest that AFSC-EVs hold regenerative ability for underdeveloped fetal lungs, demonstrating potential for therapeutic application.One Sentence SummaryFetal lung regeneration via administration of extracellular vesicles derived from amniotic fluid stem cells

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“…31 Using the nitrofen model, Tzanetakis et al derived primary epithelial cells from hypoplastic lungs and showed that amniotic fluid stem cell administration restored epithelial cellular homeostasis. 32 Yuniartha et al also tested the therapeutic effects of adult-lung-derived mesenchymal stromal cell administration in the nitrofen model and showed stem cell engraftment in the lung following maternal intrauterine vein injection. 33…”

Section: Nitrofen Modelmentioning

confidence: 99%

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

et al. 2019

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Congenital diaphragmatic hernia (CDH) is a devastating disease that still carries a high mortality and morbidity rate. Poor outcomes for fetuses and infants with CDH are mainly related to pulmonary hypoplasia (PH) and pulmonary vascular remodeling that leads to pulmonary hypertension (PHTN). Over the last five decades, research efforts have focused on modeling CDH not only to study the pathophysiology of the diaphragmatic defect, pulmonary hypoplasia, and pulmonary hypertension, but also to identify therapies that would promote lung growth and maturation, and correct vascular remodeling. As CDH is a multifactorial condition whose etiology remains unknown, there is not a single model of CDH, rather several ones that replicate different aspects of this disease. While small animals like the mouse and the rat have mainly been used to uncover biological pathways underlying the diaphragmatic defect and poor lung growth, larger animals like the lamb and the rabbit models have been instrumental for pursuing medical and surgical interventions. Overall, the use of animal models has indeed advanced our knowledge on CDH and helped us test innovative therapeutic options. For example, the lamb model of CDH has been the paradigm for testing fetal surgical procedures, including tracheal occlusion, which has been translated to clinical use. In this review, we outline the induction protocols of CDH in animals with the use of chemicals, dietary changes, genetic alterations, and surgical maneuvers, and we describe the studies that have translated experimental results to the bedside.

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Endoplasmic reticulum stress response is activated in pulmonary hypoplasia secondary to congenital diaphragmatic hernia, but is decreased by administration of amniotic fluid stem cells

Cited by 13 publications

References 34 publications

Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles

Autophagy is impaired in fetal hypoplastic lungs and rescued by administration of amniotic fluid stem cell extracellular vesicles

Impaired Fetal Lung Development can be Rescued by Administration of Extracellular Vesicles Derived from Amniotic Fluid Stem Cells

Congenital Diaphragmatic Hernia: State of the Art in Translating Experimental Research to the Bedside

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