Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction

Dravet-Gounot, Pauline; Morin, Cécile; Jacques, Sébastien; Dumont, Florent; Ely-Marius, Fabiola; Vaiman, Daniel; Jarreau, Pierre‐Henri; Méhats, Céline; Zana‐Taïeb, Elodie

doi:10.1371/journal.pone.0190445

Cited by 16 publications

(9 citation statements)

References 39 publications

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“…Interestingly, ET-1 CpG methylation was also significantly reduced in F1 IUGR rat sperm, suggesting epigenetic modifications as a potential mechanism for the multigenerational transmission of these IUGR phenotypes, via the paternal line ( 56 ). In line with this finding, altered expression of various miRNAs were found in lung tissues at day 10, day 21, and 5 months after birth of IUGR rat offspring whose mothers were either undernourished ( 68 ) or fed with a low-protein diet ( 67 ) during pregnancy. Most of these miRNAs ( miR-29, miR-128-3p, miR-34c-5p, miR-19b-3p, miR-449a-5p , and miR-30e-5p ) are involved in lung development and injury-repair ( 67 , 68 ).…”

Section: Intrauterine Growth Restriction and The Associated Altered E...supporting

confidence: 63%

“…In line with this finding, altered expression of various miRNAs were found in lung tissues at day 10, day 21, and 5 months after birth of IUGR rat offspring whose mothers were either undernourished ( 68 ) or fed with a low-protein diet ( 67 ) during pregnancy. Most of these miRNAs ( miR-29, miR-128-3p, miR-34c-5p, miR-19b-3p, miR-449a-5p , and miR-30e-5p ) are involved in lung development and injury-repair ( 67 , 68 ). Microarray analysis and homologous analysis of brain tissues containing hippocampus from growth restricted F1 rats whose mothers received a 50% reduction in food intake throughout pregnancy also revealed 49 rat genes that are homologous in humans, and had a negative correlation between gene expression and DNA methylation status ( 60 ).…”

Section: Intrauterine Growth Restriction and The Associated Altered E...supporting

confidence: 63%

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Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

2022

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A poorly functioning placenta results in impaired exchanges of oxygen, nutrition, wastes and hormones between the mother and her fetus. This can lead to restriction of fetal growth. These growth restricted babies are at increased risk of developing chronic diseases, such as type-2 diabetes, hypertension, and kidney disease, later in life. Animal studies have shown that growth restricted phenotypes are sex-dependent and can be transmitted to subsequent generations through both the paternal and maternal lineages. Altered epigenetic mechanisms, specifically changes in DNA methylation, histone modifications, and non-coding RNAs that regulate expression of genes that are important for fetal development have been shown to be associated with the transmission pattern of growth restricted phenotypes. This review will discuss the subsequent health outcomes in the offspring after growth restriction and the transmission patterns of these diseases. Evidence of altered epigenetic mechanisms in association with fetal growth restriction will also be reviewed.

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Section: Intrauterine Growth Restriction and The Associated Altered E...supporting

confidence: 63%

Section: Intrauterine Growth Restriction and The Associated Altered E...supporting

confidence: 63%

Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

2022

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“…Investigating AFSC-EV mechanism of action, we found that their beneficial effects on fetal lung tissue were exerted, at least in part, via miRNAs that regulate the expression of genes involved in lung development (5). Particularly, AFSC-EVs were highly enriched in members of the miR17~92 cluster, which is known to control lung branching morphogenesis (9), lung progenitor cell proliferation and differentiation (10,11), surfactant protein C secretion (12), and alveolarization (11). However, the mechanisms underlying the lung regenerative effects of AFSC-EV administration remain to be fully elucidated.…”

Section: Introductionmentioning

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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“…Non-coding RNA continue to be studied in the context of alveolarization, and while changes in the lung steady-state levels of mRNA, lncRNA, circRNA, and microRNA (miR) have been reported in hyperoxia-based BPD models in mice (615), the bulk of these recent studies have addressed miRs (21,419). Descriptive reports continue to emerge that associate altered steady-state levels of multiple miR species with stunted alveolarization, including IUGR (136). Temporal changes in miR-431 steady-state levels were noted during rat lung development (560), which is interesting given another in vitro study implicating miR-431-5p in surfactant expression (311).…”

Section: Non-coding Rnamentioning

confidence: 89%

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

Lignelli

Palumbo

Myti

et al. 2019

American Journal of Physiology-Lung Cellular and Molecular Phys

109

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Bronchopulmonary dysplasia (BPD) is the most common cause of morbidity and mortality in preterm infants. A key histopathological feature of BPD is stunted late lung development, where the process of alveolarization—the generation of alveolar gas exchange units—is impeded, through mechanisms that remain largely unclear. As such, there is interest in the clarification both of the pathomechanisms at play in affected lungs, and the mechanisms of de novo alveoli generation in healthy, developing lungs. A better understanding of normal and pathological alveolarization might reveal opportunities for improved medical management of affected infants. Furthermore, disturbances to the alveolar architecture are a key histopathological feature of several adult chronic lung diseases, including emphysema and fibrosis, and it is envisaged that knowledge about the mechanisms of alveologenesis might facilitate regeneration of healthy lung parenchyma in affected patients. To this end, recent efforts have interrogated clinical data, developed new—and refined existing—in vivo and in vitro models of BPD, have applied new microscopic and radiographic approaches, and have developed advanced cell-culture approaches, including organoid generation. Advances have also been made in the development of other methodologies, including single-cell analysis, metabolomics, lipidomics, and proteomics, as well as the generation and use of complex mouse genetics tools. The objective of this review is to present advances made in our understanding of the mechanisms of lung alveolarization and BPD over the period 1 January 2017–30 June 2019, a period that spans the 50th anniversary of the original clinical description of BPD in preterm infants.

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Lung microRNA deregulation associated with impaired alveolarization in rats after intrauterine growth restriction

Cited by 16 publications

References 39 publications

Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

Epigenetic Mechanisms Responsible for the Transgenerational Inheritance of Intrauterine Growth Restriction Phenotypes

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

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

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