miR-200 family expression during normal and abnormal lung development due to congenital diaphragmatic hernia at the later embryonic stage in the nitrofen rat model

Mulhall, Drew; Khoshgoo, Naghmeh; Visser, Robin; Day, Chelsea; Zhu, Fuqin; Eastwood, Patrice; Keijzer, Richard

doi:10.1007/s00383-020-04757-2

Cited by 8 publications

(6 citation statements)

References 14 publications

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“…It is well known that lung developmental processes are regulated by multiple miRNAs (11), whose expression is missing or dysregulated in experimental and human CDH lungs (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). A promising avenue to deliver a heterogenous complement of miRNAs is based on the administration of extracellular vesicles (EVs).…”

Section: Introductionmentioning

confidence: 99%

Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages

Antounians

Figueira

Kukreja

et al. 2022

Preprint

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Congenital diaphragmatic hernia (CDH) is a devastating condition characterized by incomplete closure of the diaphragm and herniation of abdominal organs into the chest. As a result, fetuses have pulmonary hypoplasia, whose severity is the main determinant of poor outcome. The pathogenesis of pulmonary hypoplasia secondary to CDH is at least in part explained by lack or dysregulation of miRNAs that are known to regulate lung developmental processes. Herein, we report that intra-amniotic administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) rescues lung growth and maturation in a fetal rat model of CDH. To understand which fetal lung cells and biological pathways are affected by AFSC-EVs, we conducted whole lung single nucleus RNA-sequencing. We discovered that CDH lungs have a multilineage inflammatory signature with macrophage enrichment, and confirmed these findings in autopsy samples of lungs from human fetuses with CDH. Transcriptomic analysis of CDH fetal rat lungs also showed that AFSC-EV treatment reduced macrophage density and inflammation to normal levels. Analyzing the miRNAs contained in the AFSC-EV cargo with validated mRNA targets, we found that the downregulated genes in AFSC-EV treated CDH lungs were involved in inflammatory response and immune system processes. This study reports a single cell atlas of normal and hypoplastic CDH fetal rat lungs and provides evidence that AFSC-EVs restore lung development by addressing multiple pathophysiological aspects of CDH.

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Section: Introductionmentioning

confidence: 99%

Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages

Antounians

Figueira

Kukreja

et al. 2022

Preprint

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“…To date, it has been shown that hypoplastic CDH lungs show a specific expression pattern of miR-200 family members [ 54 ] with dysregulated miR-200b expression in humans [ 21 ] and animal models [ 17 ].…”

Section: Discussion and Future Perspectivementioning

confidence: 99%

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension

Pugnaloni

Capolupo

Patel

et al. 2023

IJMS

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Epigenetic regulators such as microRNAs (miRNAs) have a key role in modulating several gene expression pathways and have a role both in lung development and function. One of the main pathogenetic determinants in patients with congenital diaphragmatic hernia (CDH) is pulmonary hypertension (PH), which is directly related to smaller lung size and pulmonary microarchitecture alterations. The aim of this review is to highlight the importance of miRNAs in CDH-related PH and to summarize the results covering this topic in animal and human CDH studies. The focus on epigenetic modulators of CDH-PH offers the opportunity to develop innovative diagnostic tools and novel treatment modalities, and provides a great potential to increase researchers’ understanding of the pathophysiology of CDH.

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“…29 Alongside studies analyzing samples from human CDH patients, there has been extensive literature on experimental models confirming that highly conserved miRNAs play a role in the pathogenesis of CDH associated lung underdevelopment. [29][30][31][32][33][34][35][36][37][38] One could envision that a therapy that supplements the missing miRNAs could be a potential therapeutic strategy to rescue lung underdevelopment in CDH babies (Figure 1). Given the myriad of known and unknown miRNA candidates and the complex pathological phenotype observed in CDH hypoplastic lungs, a promising avenue could be a therapy based on the administration of extracellular vesicles (EVs) that deliver a heterogenous complement of small RNA species.…”

Section: New Insights Into Molecular Mechanisms Of Pulmonary Hypoplas...mentioning

confidence: 99%

“…These miRNAs are involved in pulmonary branching morphogenesis and have also been reported to be dysregulated in the rat nitrofen model of CDH 29 . Alongside studies analyzing samples from human CDH patients, there has been extensive literature on experimental models confirming that highly conserved miRNAs play a role in the pathogenesis of CDH associated lung underdevelopment 29–38 …”

Section: New Insights Into Molecular Mechanisms Of Pulmonary Hypoplas...mentioning

confidence: 99%

Fetal lung regeneration using stem cell‐derived extracellular vesicles: A new frontier for pulmonary hypoplasia secondary to congenital diaphragmatic hernia

et al. 2022

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The poor outcomes of babies with congenital diaphragmatic hernia (CDH) are directly related to pulmonary hypoplasia, a condition characterized by impaired lung development. Although the pathogenesis of pulmonary hypoplasia is not fully elucidated, there is now evidence that CDH patients have missing or dysregulated microRNAs (miRNAs) that regulate lung development. A prenatal therapy that supplements these missing/dysregulated miRNAs could be a strategy to rescue normal lung development. Extracellular vesicles (EVs), also known as exosomes when of small dimensions, are lipid‐bound nanoparticles that can transfer their heterogeneous cargo (proteins, lipids, small RNAs) to target cells to induce biological responses. Herein, we review all studies that show evidence for stem cell‐derived EVs as a regenerative therapy to rescue normal development in CDH fetal lungs. Particularly, we report studies showing that administration of EVs derived from amniotic fluid stem cells (AFSC‐EVs) to models of pulmonary hypoplasia promotes fetal lung growth and maturation via transfer of miRNAs that are known to regulate lung developmental processes. We also describe that stem cell‐derived EVs exert effects on vascular remodeling, thus possibly preventing postnatal pulmonary hypertension. Finally, we discuss future perspectives and challenges to translate this promising stem cell EV‐based therapy to clinical practice.

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miR-200 family expression during normal and abnormal lung development due to congenital diaphragmatic hernia at the later embryonic stage in the nitrofen rat model

Cited by 8 publications

References 14 publications

Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages

Administration of amniotic fluid stem cell extracellular vesicles promotes development of fetal hypoplastic lungs by immunomodulating lung macrophages

Role of microRNAs in Congenital Diaphragmatic Hernia-Associated Pulmonary Hypertension

Fetal lung regeneration using stem cell‐derived extracellular vesicles: A new frontier for pulmonary hypoplasia secondary to congenital diaphragmatic hernia

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