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    Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia
    (2020)
    Francesca Maria Russo
    ;
    Marina Gabriela Monteiro Carvalho Mori Da Cunha
    ;
    Julio Jimenez  
    ;
    Flore Lesage
    ;
    Mary Patrice Eastwood
    <jats:sec> <jats:title>Objective:</jats:title> <jats:p>To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, <jats:italic toggle="yes">P</jats:italic>=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm<jats:sup>2</jats:sup> vs 3.5 ± 0.9 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.043) and lung mechanics (static elastance 61 ± 36 cmH<jats:sub>2</jats:sub>O /mL vs 113 ± 40 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.001 and 31 ± 9 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.</jats:p> </jats:sec>
      3Scopus© Citations 19
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    Complementary Effect of Maternal Sildenafil and Fetal Tracheal Occlusion Improves Lung Development in the Rabbit Model of Congenital Diaphragmatic Hernia
    (2020)
    Francesca Maria Russo
    ;
    Marina Gabriela Monteiro Carvalho Mori Da Cunha
    ;
    Julio Jimenez  
    ;
    Flore Lesage
    ;
    Mary Patrice Eastwood
    <jats:sec> <jats:title>Objective:</jats:title> <jats:p>To evaluate the effect of combining antenatal sildenafil with fetal tracheal occlusion (TO) in fetal rabbits with surgically induced congenital diaphragmatic hernia (CDH).</jats:p> </jats:sec> <jats:sec> <jats:title>Background:</jats:title> <jats:p>Although antenatal sildenafil administration rescues vascular abnormalities in lungs of fetal rabbits with CDH, it only partially improves airway morphometry. We hypothesized that we could additionally stimulate lung growth by combining this medical treatment with fetal TO.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p>CDH was created on gestational day (GD)23 (n=54). Does were randomized to receive either sildenafil 10 mg/kg/d or placebo by subcutaneous injection from GD24 to GD30. On GD28, fetuses were randomly assigned to TO or sham neck dissection. At term (GD30) fetuses were delivered, ventilated, and finally harvested for histological and molecular analyses. Unoperated littermates served as controls.</jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p>The lung-to-body-weight ratio was significantly reduced in sham-CDH fetuses either (1.2 ± 0.3% vs 2.3 ± 0.3% in controls, <jats:italic toggle="yes">P</jats:italic>=0.0003). Sildenafil had no effect on this parameter, while CDH fetuses undergoing TO had a lung-to-body-weight ratio comparable to that of controls (2.5 ± 0.8%, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001). Sildenafil alone induced an improvement in the mean terminal bronchiolar density (2.5 ± 0.8 br/mm<jats:sup>2</jats:sup> vs 3.5 ± 0.9 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.043) and lung mechanics (static elastance 61 ± 36 cmH<jats:sub>2</jats:sub>O /mL vs 113 ± 40 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>=0.008), but both effects were more pronounced in fetuses undergoing additional TO (2.1 ± 0.8 br/mm<jats:sup>2</jats:sup>, <jats:italic toggle="yes">P</jats:italic>=0.001 and 31 ± 9 cmH<jats:sub>2</jats:sub>O/mL, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001 respectively). Both CDH-sham and CDH-TO fetuses treated with placebo had an increased medial wall thickness of peripheral pulmonary vessels (41.9 ± 2.9% and 41.8 ± 3.2%, vs 24.0 ± 2.9% in controls, <jats:italic toggle="yes">P</jats:italic>&lt;0.0001). CDH fetuses treated with sildenafil, either with or without TO, had a medial thickness in the normal range (29.4% ± 2.6%). Finally, TO reduced gene expression of vascular endothelial growth factor and surfactant protein A and B, but this effect was counteracted by sildenafil.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion:</jats:title> <jats:p>In the rabbit model for CDH, the combination of maternal sildenafil and TO has a complementary effect on vascular and parenchymal lung development.</jats:p> </jats:sec>
      1Scopus© Citations 19
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    The amniotic fluid as a source of mesenchymal stem cells with lung‐specific characteristics
    (2017)
    Flore Lesage
    ;
    Silvia Zia
    ;
    JIMENEZ GREZ, JULIO ALBERTO  
    ;
    Jan Deprest
    ;
    Jaan Toelen
    <jats:p>What is already known about this topic? <jats:list list-type="bullet"> <jats:list-item><jats:p>Fetal tissues are interesting sources of stem cells for autologous therapy in a neonatal context.</jats:p></jats:list-item> <jats:list-item><jats:p>AF‐MSC are a heterogeneous stem cell population of which the exact origin remains elusive.</jats:p></jats:list-item> </jats:list></jats:p><jats:p>What does this study add? <jats:list list-type="bullet"> <jats:list-item><jats:p>This study identifies AF‐MSC with lung‐specific characteristics.</jats:p></jats:list-item> <jats:list-item><jats:p>This study provides a reliable culture method that supports the expansion of lung‐specific AF‐MSC.</jats:p></jats:list-item> </jats:list></jats:p>
      8Scopus© Citations 6
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    Scopus© Citations 7  4
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    Scopus© Citations 12  1
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    Modulation of the Early Host Response to Electrospun Polylactic Acid Matrices by Mesenchymal Stem Cells from the Amniotic Fluid
    (2018)
    Flore Lesage
    ;
    Sabiniano Roman
    ;
    Savitree Pranpanus
    ;
    Simona Ospitalieri
    ;
    Silvia Zia
    <jats:p> Purpose The reconstruction of congenital diaphragmatic hernia or other congenital soft tissue defects often requires implants. These can be either degradable or permanent, each having their advantages. Whatever type is being used, the host response induced by implants plays a crucial role to determine the outcome. Macrophages are pivotal during implant remodeling; they are plastic and acquire in response to environmental stimuli either an inflammatory status and mediate subsequent fibrosis or a regulatory status and facilitate functional remodeling. Matrices engineered with mesenchymal stem cells (MSCs) have the capacity to modulate the host immune reaction. MSCs are believed to promote constructive remodeling of the implant through a regulatory macrophage response among others. Herein, we evaluate this potential of MSC derived from the amniotic fluid (AF-MSC), an interesting MSC type for neonatal reconstruction, on electrospun polylactic acid (PLA) scaffolds.</jats:p><jats:p> Methods We seeded AF-MSC at a density of 1.105/cm2 on electrospun PLA matrices and determined cell viability. In vivo, we used cell-seeded or cell-free PLA matrices for subcutaneous implantation in immune competent rats. The host immune response was evaluated by histomorphometry at 14 days postoperatively.</jats:p><jats:p> Results The PLA matrix supported adherence and proliferation of AF-MSC. Fourteen days after implantation, PLA matrices were well penetrated by inflammatory cells, new blood vessels, and collagen fibers. AF-MSC–seeded scaffolds were associated with a similar response yet with a decreased number of eosinophils, increased matrix degradation and collagen fiber deposition compared with controls. The amount of total macrophages and of M2-subtype was similar for all animals.</jats:p><jats:p> Conclusion Electrospun PLA matrices are a suitable substrate for short-term culture of AF-MSC. In rats, addition of AF-MSC to PLA matrices modulates the host response after subcutaneous implantation, yet without a difference in macrophage profile compared with control.</jats:p>
      6Scopus© Citations 6
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    Upregulation of Vascular Endothelial Growth Factor in Amniotic Fluid Stem Cells Enhances Their Potential to Attenuate Lung Injury in a Preterm Rabbit Model of Bronchopulmonary Dysplasia
    (2018)
    JIMENEZ GREZ, JULIO ALBERTO  
    ;
    Flore Lesage
    ;
    Jute Richter
    ;
    Taro Nagatomo
    ;
    Thomas Salaets
    <jats:p>&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Bronchopulmonary dysplasia (BPD) is a chronic lung disease that affects extremely preterm infants and remains – despite improvements in neonatal intensive care – a major cause of neonatal mortality and morbidity. Cell-therapeutic strategies employing mesenchymal stem cells (MSC) have been shown to modulate lung development in BPD models. &lt;b&gt;&lt;i&gt;Objective:&lt;/i&gt;&lt;/b&gt; Herein, we evaluate the potential of human amniotic fluid (hAF)-SC and hAF-SC with upregulated expression of vascular endothelial growth factor (VEGF) as cell-therapeutic agents for BPD. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Preterm rabbit pups were raised in normoxia (21% O&lt;sub&gt;2&lt;/sub&gt;) or hyperoxia (≥95% O&lt;sub&gt;2&lt;/sub&gt;). Hyperoxia-exposed pups randomly received an intraperitoneal injection of fibroblasts, naïve hAF-SC, or hAF-SC-VEGF on postnatal day (PN) 0. On PN7, surviving pups were tested for pulmonary (forced oscillation technique) and vascular (pulmonary artery Doppler ultrasound) function, and lungs were processed for morphometric measurements of parenchymal and vascular structure and inflammation. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Intraperitoneal injection of cells resulted in homing to the lungs. The lungs of hyperoxia-exposed animals displayed parenchymal and vascular structural and functional damage reminiscent of BPD, which was significantly improved after treatment with hAF-SC-VEGF. Treating hyperoxia-exposed animals with naïve AF-SC attenuated only the lung inflammation and the vascular structural defect. Treatment with fibroblasts, which were used as a cellular control, did not lead to any improvements. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; hAF-SC with upregulated VEGF expression display enhanced potential to prevent/reverse lung injury in preterm rabbits, whereas naïve hAF-SC only show a moderate therapeutic potential. These results point towards an added value of VEGF delivered by hAF-SC in the treatment of BPD.</jats:p>
    Scopus© Citations 19  8