Anti-inflammatory Effects of Antenatal Administration of Stem Cell Derived extracellular Vesicles in the Brain of Rat Fetuses with Congenital Diaphragmatic Hernia

Overview

Journal Pediatr Surg Int

Specialties General Surgery
Pediatrics

Date 2023 Nov 13

PMID 37955723

Authors

Matisse Blundell

Fabian Doktor

Rebeca L Figueira

Kasra Khalaj

George Biouss

Lina Antounians

Augusto Zani

Affiliations

Soon will be listed here.

Abstract

Purpose: Congenital diaphragmatic hernia (CDH) survivors may experience neurodevelopmental impairment, whose etiology remains elusive. Preclinical evidence indicates that amniotic fluid stem cell extracellular vesicle (AFSC-EV) administration promotes lung development but their effects on other organs are unknown. Herein, we investigated the brain of rat fetuses with CDH for signs of inflammation and response to AFSC-EVs.

Methods: CDH was induced by maternal nitrofen administration at E9.5. At E18.5, fetuses were injected intra-amniotically with saline or AFSC-EVs (isolated by ultracentrifugation, characterized as per MISEV guidelines). Fetuses from vehicle-gavaged dams served as controls. Groups were compared for: lung hypoplasia, TNFa and IL-1B brain expression, and activated microglia (Iba1) density in the subgranular zone (SGZ).

Results: CDH lungs had fewer airspaces compared to controls, whereas AFSC-EV-treated lungs had rescued branching morphogenesis. Fluorescently labeled AFSC-EVs injected intra-amniotically into CDH fetuses had fluorescent signal in the brain. Compared to controls, the brain of CDH fetuses had higher TNFa and IL-1B levels, and increased activated microglia density. Conversely, the brain of AFSC-EV treated fetuses had inflammatory marker expression levels and microglia density similar to controls.

Conclusion: This study shows that the brain of rat fetuses with CDH has signs of inflammation that are abated by the intra-amniotic administration of AFSC-EVs.

Citing Articles

Amniotic fluid stem cell extracellular vesicles as a novel fetal therapy for pulmonary hypoplasia: a review on mechanisms and translational potential.

Doktor F, Antounians L, Figueira R, Khalaj K, Duci M, Zani A Stem Cells Transl Med. 2025; 14(1.

PMID: 39823257 PMC: 11740888. DOI: 10.1093/stcltm/szae095.

Sex-specific differences in the severity of pulmonary hypoplasia in experimental congenital diaphragmatic hernia and implications for extracellular vesicle-based therapy.

Doktor F, Lo E, Fortuna V, Khalaj K, Garcia M, Figueira R Pediatr Surg Int. 2024; 40(1):278.

PMID: 39467854 DOI: 10.1007/s00383-024-05856-0.

Fetal hypoplastic lungs have multilineage inflammation that is reversed by amniotic fluid stem cell extracellular vesicle treatment.

Antounians L, Figueira R, Kukreja B, Litvack M, Zani-Ruttenstock E, Khalaj K Sci Adv. 2024; 10(30):eadn5405.

PMID: 39058789 PMC: 11277482. DOI: 10.1126/sciadv.adn5405.

Therapeutic potential of extracellular vesicles derived from human amniotic epithelial cells for perinatal cerebral and pulmonary injury.

Kumar N, Bidkhori H, Yawno T, Lim R, Inocencio I Stem Cells Transl Med. 2024; 13(8):711-723.

PMID: 38895873 PMC: 11328935. DOI: 10.1093/stcltm/szae037.

References

Zani A, Chung W, Deprest J, Harting M, Jancelewicz T, Kunisaki S . Congenital diaphragmatic hernia. Nat Rev Dis Primers. 2022; 8(1):37. DOI: 10.1038/s41572-022-00362-w. View

Montalva L, Raffler G, Riccio A, Lauriti G, Zani A . Neurodevelopmental impairment in children with congenital diaphragmatic hernia: Not an uncommon complication for survivors. J Pediatr Surg. 2019; 55(4):625-634. DOI: 10.1016/j.jpedsurg.2019.05.021. View

Van der Veeken L, Russo F, Litwinska E, Gomez O, Emam D, Lewi L . Prenatal cerebellar growth is altered in congenital diaphragmatic hernia on ultrasound. Prenat Diagn. 2021; 42(3):330-337. DOI: 10.1002/pd.5993. View

Kosiv K, Moon-Grady A, Hogan W, Keller R, Rapoport R, Rogers E . Fetal cerebrovascular impedance is reduced in left congenital diaphragmatic hernia. Ultrasound Obstet Gynecol. 2020; 57(3):386-391. PMC: 7431368. DOI: 10.1002/uog.21992. View

Machado-Rivas F, Choi J, Bedoya M, Acosta Buitrago L, Velasco-Annis C, Afacan O . Brain growth in fetuses with congenital diaphragmatic hernia. J Neuroimaging. 2023; 33(4):617-624. PMC: 10363187. DOI: 10.1111/jon.13096. View

Radhakrishnan R, Merhar S, Burns P, Zhang B, Lim F, Kline-Fath B . Fetal brain morphometry on prenatal magnetic resonance imaging in congenital diaphragmatic hernia. Pediatr Radiol. 2018; 49(2):217-223. DOI: 10.1007/s00247-018-4272-z. View

Emam D, Aertsen M, Van der Veeken L, Fidon L, Patkee P, Kyriakopoulou V . Longitudinal MRI Evaluation of Brain Development in Fetuses with Congenital Diaphragmatic Hernia around the Time of Fetal Endotracheal Occlusion. AJNR Am J Neuroradiol. 2023; 44(2):205-211. PMC: 9891331. DOI: 10.3174/ajnr.A7760. View

Johng S, Licht D, Hedrick H, Rintoul N, Linn R, Gebb J . Prenatal Brain Maturation is Delayed in Neonates with Congenital Diaphragmatic Hernia. J Pediatr. 2023; 264:113738. DOI: 10.1016/j.jpeds.2023.113738. View

Wagner R, Amonkar G, Wang W, Shui J, Bankoti K, Tse W . A Tracheal Aspirate-derived Airway Basal Cell Model Reveals a Proinflammatory Epithelial Defect in Congenital Diaphragmatic Hernia. Am J Respir Crit Care Med. 2023; 207(9):1214-1226. PMC: 10161756. DOI: 10.1164/rccm.202205-0953OC. View

10.

Varisco B . Nuclear Factor-κB Keeps Basal Cells Undifferentiated in Congenital Diaphragmatic Hernia. Am J Respir Crit Care Med. 2023; 207(9):1122-1123. PMC: 10161750. DOI: 10.1164/rccm.202302-0290ED. View

11.

Shima H, Ohshiro K, Taira Y, Miyazaki E, Oue T, Puri P . Antenatal dexamethasone suppresses tumor necrosis factor-alpha expression in hypoplastic lung in nitrofen-induced diaphragmatic hernia in rats. Pediatr Res. 1999; 46(5):633-7. DOI: 10.1203/00006450-199911000-00023. View

12.

Schaible T, Reineke J, Gortner L, Monz D, Schaffelder R, Tutdibi E . Are Cytokines Useful Biomarkers to Determine Disease Severity in Neonates with Congenital Diaphragmatic Hernia?. Am J Perinatol. 2016; 34(7):648-654. DOI: 10.1055/s-0036-1597133. View

13.

Herrera-Rivero M, Zhang R, Heilmann-Heimbach S, Mueller A, Bagci S, Dresbach T . Circulating microRNAs are associated with Pulmonary Hypertension and Development of Chronic Lung Disease in Congenital Diaphragmatic Hernia. Sci Rep. 2018; 8(1):10735. PMC: 6048121. DOI: 10.1038/s41598-018-29153-8. View

14.

Perry R, Stein J, Young G, Ramanathan R, Seri I, Klee L . Antithrombin III administration in neonates with congenital diaphragmatic hernia during the first three days of extracorporeal membrane oxygenation. J Pediatr Surg. 2013; 48(9):1837-42. DOI: 10.1016/j.jpedsurg.2012.11.037. View

15.

Pavcnik-Arnol M, Bonac B, Groselj-Grenc M, Derganc M . Changes in serum procalcitonin, interleukin 6, interleukin 8 and C-reactive protein in neonates after surgery. Eur J Pediatr Surg. 2010; 20(4):262-6. DOI: 10.1055/s-0030-1253358. View

16.

Fleck S, Bautista G, Keating S, Lee T, Keller R, Moon-Grady A . Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia. Pediatr Res. 2013; 74(3):290-8. PMC: 4164304. DOI: 10.1038/pr.2013.98. View

17.

Okawada M, Kobayashi H, Tei E, Okazaki T, Lane G, Yamataka A . Serum monocyte chemotactic protein-1 levels in congenital diaphragmatic hernia. Pediatr Surg Int. 2007; 23(5):487-91. DOI: 10.1007/s00383-006-1858-6. View

18.

Khalaj K, Antounians L, Figueira R, Post M, Zani A . Autophagy Is Impaired in Fetal Hypoplastic Lungs and Rescued by Administration of Amniotic Fluid Stem Cell Extracellular Vesicles. Am J Respir Crit Care Med. 2022; 206(4):476-487. DOI: 10.1164/rccm.202109-2168OC. View

19.

Khalaj K, Figueira R, Antounians L, Gandhi S, Wales M, Montalva L . Treatment with Amniotic Fluid Stem Cell Extracellular Vesicles Promotes Fetal Lung Branching and Cell Differentiation at Canalicular and Saccular Stages in Experimental Pulmonary Hypoplasia Secondary to Congenital Diaphragmatic Hernia. Stem Cells Transl Med. 2022; 11(10):1089-1102. PMC: 9585953. DOI: 10.1093/stcltm/szac063. View

20.

Antounians L, Tzanetakis A, Pellerito O, Catania V, Sulistyo A, Montalva L . The Regenerative Potential of Amniotic Fluid Stem Cell Extracellular Vesicles: Lessons Learned by Comparing Different Isolation Techniques. Sci Rep. 2019; 9(1):1837. PMC: 6372651. DOI: 10.1038/s41598-018-38320-w. View