An intra-amniotic injection of mesenchymal stem cells promotes lung maturity in a rat congenital diaphragmatic hernia model

Takayama, Shohei; Sakai, Kohei; Fumino, Shigehisa; Furukawa, Taiji; Kishida, Tsunao; Mazda, Osam; Tajiri, Tatsuro

doi:10.1007/s00383-019-04561-7

Cited by 17 publications

(7 citation statements)

References 24 publications

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“…In this study, we initially tested three routes and ultimately opted for AFSC-EV intra-amniotic injection during the saccular stage of lung development. At this timepoint, clustered fetal breathing movements occur at ~40 movements/hour in fetal rats (108) and intra-amniotically injected products reach the fetal lung, as reported (27,(109)(110)(111).…”

Section: )supporting

confidence: 58%

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: )supporting

confidence: 58%

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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“…Human mesenchymal stem cells (hMSCs) were used to treat rats with nitrogen-induced congenital diaphragmatic hernias (CDH-hMSCs group), which showed a higher survival rate, larger air spaces, and thinner alveolar walls than those in a control CDH group. 35 Previously, we demonstrated that intraamniotic bone marrow-derived mesenchymal stem cell (BMSC) injections into rats during the early development of neural tube defects (NTDs) may promote functional recovery. 36 In further studies, we treated rats with NTDs with intraamniotic microinjection of BMSCs and collapsin response mediator protein 4 (CRMP4) siRNA.…”

Section: Discussionmentioning

confidence: 99%

Anti-miR-141-3p maintains homeostasis between autophagy and apoptosis by targeting Yy1 in the fetal lumbosacral defecation center of rats

Li,

Liu,

Yao

et al. 2024

Molecular Therapy - Nucleic Acids

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“…Yuniartha et al administered lung tissue MSCs from donor adult rats to nitrofen-exposed rats via a single uterine vein injection ( 119 ), and found that in addition to alleviating pulmonary hypoplasia, the treated CDH group also had reduced medial wall thickening compared to the nitrofen-only group. Similarly, Takayama et al demonstrated decreased wall muscularization in nitrofen-exposed rats following intra-amniotic injection of human MSCs ( 120 ). An ex vivo study examined explanted nitrofen-exposed rat lungs, which were conditioned in amniotic fluid-derived MSC media, and found increased VEGF and fibroblast growth factor expression compared to controls ( 121 ).…”

Section: Antenatal Regenerative Therapies For Cdh-phmentioning

confidence: 94%

Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models

et al. 2020

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Congenital diaphragmatic hernia (CDH)-related deaths are the largest contributor of in-hospital neonatal deaths in children with congenital malformations. Morbidity and mortality in CDH are directly related to the development of pulmonary hypertension (PH). Current treatment consists of supportive measures. To date, no pharmacotherapy has been shown to effectively reverse the hallmark finding of pulmonary vascular remodeling that is associated with pulmonary hypertension in CDH (CDH-PH). As such, there is a great need for novel therapies to effectively manage CDH-PH. Our review aims to evaluate emerging therapies, and specifically focuses on those that are still under investigation and not approved for clinical use by the Food and Drug Administration. Therapies were categorized into antenatal pharmacotherapies or antenatal regenerative therapies and assessed on their method of administration, safety profile, effect on pulmonary vascular pathophysiology, and overall efficacy. In general, emerging antenatal pharmaceutical and regenerative treatments primarily aim to alleviate pulmonary vascular remodeling by restoring normal function and levels of key regulatory factors involved in pulmonary vascular development and/or in promoting angiogenesis. Overall, while these emerging therapies show great promise for the management of CDH-PH, most require further assessment of safety and efficacy in preclinical models before translation into the clinical setting.

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An intra-amniotic injection of mesenchymal stem cells promotes lung maturity in a rat congenital diaphragmatic hernia model

Cited by 17 publications

References 24 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

Anti-miR-141-3p maintains homeostasis between autophagy and apoptosis by targeting Yy1 in the fetal lumbosacral defecation center of rats

Emerging antenatal therapies for congenital diaphragmatic hernia-induced pulmonary hypertension in preclinical models

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