Dataset Information

Assessing the impact of gestational age of donors on the efficacy of amniotic epithelial cell-derived extracellular vesicles in experimental bronchopulmonary dysplasia.

ABSTRACT:

Background and rationale

Extracellular vesicles (EVs) are a potential cell-free regenerative medicine. Human amniotic epithelial cells (hAECs) are a viable source of cell therapy for diseases like bronchopulmonary dysplasia (BPD). However, little is known about the impact of gestational age of the donor on the quality of hAEC-derived EVs.

Aims

To determine the impact of gestational age on hAEC-derived EVs in experimental BPD.

Results

Term hAEC-derived EVs displayed a significantly higher density of surface epitopes (CD142 and CD133) and induced greater macrophage phagocytosis compared to preterm hAEC-EVs. However, T cell proliferation was more significantly suppressed by preterm hAEC-EVs. Using a model of experimental BPD, we observed that term but not preterm hAEC-EVs improved tissue-to-airspace ratio and septal crest density. While both term and preterm hAEC-EVs reduced the levels of inflammatory cytokines on postnatal day 7, the improvement in lung injury was associated with increased type II alveolar cells which was only observed in term hAEC-EV treatment group. Furthermore, only neonatal term hAEC-EVs reduced airway hyper-responsiveness, mitigated pulmonary hypertension and protected against right ventricular hypertrophy at 6 weeks of age.

Conclusion

Term hAEC-EVs, but not preterm hAEC-EVs, have therapeutic efficacy in a mouse model of BPD-like lung injury. Therefore, the impact of donor criteria should be considered when applying perinatal cells-derived EV therapy for clinical use.

SUBMITTER: Zhu D

PROVIDER: S-EPMC9102678 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Publications

Assessing the impact of gestational age of donors on the efficacy of amniotic epithelial cell-derived extracellular vesicles in experimental bronchopulmonary dysplasia.

Zhu Dandan D Krause Mirja M Yawno Tamara T Kusuma Gina D GD Schwab Renate R Barabadi Mehri M Maleken Amina S AS Chan Siow T ST Hunt Rod R Greening David D Wallace Euan M EM Lim Rebecca R

Stem cell research & therapy 20220512 1

<h4>Background and rationale</h4>Extracellular vesicles (EVs) are a potential cell-free regenerative medicine. Human amniotic epithelial cells (hAECs) are a viable source of cell therapy for diseases like bronchopulmonary dysplasia (BPD). However, little is known about the impact of gestational age of the donor on the quality of hAEC-derived EVs.<h4>Aims</h4>To determine the impact of gestational age on hAEC-derived EVs in experimental BPD.<h4>Results</h4>Term hAEC-derived EVs displayed a signif ...[more]

PMID: 35550006

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Project description:BACKGROUND:Mesenchymal stem cells (MSCs) are promising tools for the treatment of human lung disease and other pathologies relevant to newborn medicine. Recent studies have established MSC exosomes (EXO), as one of the main therapeutic vectors of MSCs in mouse models of multifactorial chronic lung disease of preterm infants, bronchopulmonary dysplasia (BPD). However, the mechanisms underlying MSC-EXO therapeutic action are not completely understood. Using a neonatal mouse model of human BPD, we evaluated the therapeutic efficiency of early gestational age (GA) human umbilical cord (hUC)-derived MSC EXO fraction and its exosomal factor, tumor necrosis factor alpha-stimulated gene-6 (TSG-6). METHODS:Conditioned media (CM) and EXO fractions were isolated from 25 and 30 weeks GA hUC-MSC cultures grown in serum-free media (SFM) for 24 h. Newborn mice were exposed to hyperoxia (> 95% oxygen) and were given intraperitoneal injections of MSC-CM or MSC-CM EXO fractions at postnatal (PN) day 2 and PN4. They were then returned to room air until PN14 (in a mouse model of severe BPD). The treatment regime was followed with (rh)TSG-6, TSG-6-neutralizing antibody (NAb), TSG-6 (si)RNA-transfected MSC-CM EXO and their appropriate controls. Echocardiography was done at PN14 followed by harvesting of lung, heart and brain for assessment of pathology parameters. RESULTS:Systemic administration of CM or EXO in the neonatal BPD mouse model resulted in robust improvement in lung, cardiac and brain pathology. Hyperoxia-exposed BPD mice exhibited pulmonary inflammation accompanied by alveolar-capillary leakage, increased chord length, and alveolar simplification, which was ameliorated by MSC CM/EXO treatment. Pulmonary hypertension and right ventricular hypertrophy was also corrected. Cell death in brain was decreased and the hypomyelination reversed. Importantly, we detected TSG-6, an immunomodulatory glycoprotein, in EXO. Administration of TSG-6 attenuated BPD and its associated pathologies, in lung, heart and brain. Knockdown of TSG-6 by NAb or by siRNA in EXO abrogated the therapeutic effects of EXO, suggesting TSG-6 as an important therapeutic molecule. CONCLUSIONS:Preterm hUC-derived MSC-CM EXO alleviates hyperoxia-induced BPD and its associated pathologies, in part, via exosomal factor TSG-6. The work indicates early systemic intervention with TSG-6 as a robust option for cell-free therapy, particularly for treating BPD.

Project description:BackgroundMicrobiome dysbiosis can have long-lasting effects on our health and induce the development of various diseases. Bronchopulmonary dysplasia (BPD) is a multifactorial disease with pre- and postnatal origins including intra-amniotic infection as main risk factor. Recently, postnatal pathologic lung microbiota colonization was associated with BPD. The objectives of this prospective observational cohort study were to describe differences in bacterial signatures in the amniotic fluid (AF) of intact pregnancies without clinical signs or risk of preterm delivery and AF samples obtained during preterm deliveries and their variations between different BPD disease severity stages.MethodsAF samples were collected under sterile conditions during fetal intervention from intact pregnancies (n = 17) or immediately before preterm delivery < 32 weeks (n = 126). Metabarcoding based approaches were used for the molecular assessment of bacterial 16S rRNA genes to describe bacterial community structure.ResultsThe absolute amount of 16S rRNA genes was significantly increased in AF of preterm deliveries and detailed profiling revealed a reduced alpha diversity and a significant change in beta diversity with a reduced relative abundance of 16S rRNA genes indicative for Lactobacillus and Acetobacter while Fusobacterium, Pseudomonas, Ureaplasma and Staphylococcus 16S rRNA gene prevailed. Although classification of BPD by disease severity revealed equivalent absolute 16S rRNA gene abundance and alpha and beta diversity in no, mild and moderate/severe BPD groups, for some 16S rRNA genes differences were observed in AF samples. Bacterial signatures of infants with moderate/severe BPD showed predominance of 16S rRNA genes belonging to the Escherichia-Shigella cluster while Ureaplasma and Enterococcus species were enriched in AF samples of infants with mild BPD.ConclusionsOur study identified distinct and diverse intrauterine 16S rRNA gene patterns in preterm infants immediately before birth, differing from the 16S rRNA gene signature of intact pregnancies. The distinct 16S rRNA gene signatures at birth derive from bacteria with varying pathogenicity to the immature lung and are suited to identify preterm infants at risk. Our results emphasize the prenatal impact to the origins of BPD.

Project description:A naturally occurring single nucleotide polymorphism (SNP), (R213G), in extracellular superoxide dismutase (SOD3), decreases SOD3 matrix binding affinity. Humans and mature mice expressing the R213G SNP exhibit increased cardiovascular disease but decreased lung disease. The impact of this SNP on the neonatal lung at baseline or with injury is unknown. Wild type and homozygous R213G mice were injected with intraperitoneal bleomycin or phosphate buffered saline (PBS) three times weekly for three weeks and tissue harvested at 22 days of life. Vascular and alveolar development were evaluated by morphometric analysis and immunostaining of lung sections. Pulmonary hypertension (PH) was assessed by right ventricular hypertrophy (RVH). Lung protein expression for superoxide dismutase (SOD) isoforms, catalase, vascular endothelial growth factor receptor 2 (VEGFR2), endothelial nitric oxide synthase (eNOS) and guanosine triphosphate cyclohydrolase-1 (GTPCH-1) was evaluated by western blot. SOD activity and SOD3 expression were measured in serum. In R213G mice, SOD3 lung protein expression decreased, serum SOD3 protein expression and SOD serum activity increased compared to wild type (WT) mice. Under control conditions, R213G mice developed pulmonary vascular remodeling (decreased vessel density and increased medial wall thickness) and PH; alveolar development was similar between strains. After bleomycin injury, in contrast to WT, R213G mice were protected from impaired alveolar development and their vascular abnormalities and PH did not worsen. Bleomycin decreased VEGFR2 and GTPCH-1 only in WT mice. R213G neonatal mice demonstrate impaired vascular development and PH at baseline without alveolar simplification, yet are protected from bleomycin induced lung injury and worsening of pulmonary vascular remodeling and PH. These results show that vessel bound SOD3 is essential in normal pulmonary vascular development, and increased serum SOD3 expression and SOD activity prevent lung injury in experimental bronchopulmonary dysplasia (BPD) and PH.

Dataset Information

Assessing the impact of gestational age of donors on the efficacy of amniotic epithelial cell-derived extracellular vesicles in experimental bronchopulmonary dysplasia.

Background and rationale

Aims

Results

Conclusion

Publications

Assessing the impact of gestational age of donors on the efficacy of amniotic epithelial cell-derived extracellular vesicles in experimental bronchopulmonary dysplasia.

Similar Datasets

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