Attenuated
            <scp>PDGF</scp>
            signaling drives alveolar and microvascular defects in neonatal chronic lung disease

Oak, Prajakta; Pritzke, Tina; Thiel, Isabella; Koschlig, Markus; Mous, Daphne S.; Windhorst, Anita; Jain, Noopur; Eickelberg, Oliver; Foerster, Kai; Schulze, Andreas; Goepel, Wolfgang; Reicherzer, Tobias; Ehrhardt, Harald; Rottier, Robbert J.; Ahnert, Peter; Gortner, Ludwig; Desai, Tushar J.; Hilgendorff, Anne

doi:10.15252/emmm.201607308

Cited by 38 publications

(42 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alveolar myofibroblasts, which express aSMA, facilitate alveolarization (Vaccaro & Brody, 1978;Morrisey & Hogan, 2010;Hogan et al, 2014) by generating elastin cables that drive formation of secondary septa, which divide existing airspaces by squeezing the pre-existing alveoli with an elastin net, or pulling septal invaginations into airspaces (Branchfield et al, 2016). Myofibroblasts localize to alveolar entry rings during alveolarization (McGowan et al, 2008;Ntokou et al, 2015), exhibit phenotypic plasticity (Endale et al, 2017;McGowan & McCoy, 2017) and are marked by platelet-derived growth factor (PDGF) receptor (PDGFR)a, a mediator of normal (Boström et al, 1996(Boström et al, , 2002Gouveia et al, 2018) and aberrant (Oak et al, 2017) alveologenesis. Reduced levels of PDGFRa have also been noted in mesenchymal cells from human neonates that develop BPD (Popova et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

et al. 2019

View full text Add to dashboard Cite

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth characterized by arrested lung alveolarization, which generates lungs that are incompetent for effective gas exchange. We report here deregulated expression of miR‐34a in a hyperoxia‐based mouse model of BPD, where miR‐34a expression was markedly increased in platelet‐derived growth factor receptor (PDGFR)α‐expressing myofibroblasts, a cell type critical for proper lung alveolarization. Global deletion of miR‐34a; and inducible, conditional deletion of miR‐34a in PDGFRα+ cells afforded partial protection to the developing lung against hyperoxia‐induced perturbations to lung architecture. Pdgfra mRNA was identified as the relevant miR‐34a target, and using a target site blocker in vivo, the miR‐34a/Pdgfra interaction was validated as a causal actor in arrested lung development. An antimiR directed against miR‐34a partially restored PDGFRα+ myofibroblast abundance and improved lung alveolarization in newborn mice in an experimental BPD model. We present here the first identification of a pathology‐relevant microRNA/mRNA target interaction in aberrant lung alveolarization and highlight the translational potential of targeting the miR‐34a/Pdgfra interaction to manage arrested lung development associated with preterm birth.

show abstract

Section: Introductionmentioning

confidence: 99%

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The inflammatory overweight turns the signaling pathway equilibrium into a self-perpetuating disbalance and exaggerated NF κ B signaling which boosts inflammation and inflammatory cell survival and aggravates the distortion of the central pathways of lung development. PDGF receptor α , bone morphogenetic protein, fibroblast growth factors, PDGFR- α , Wnt/ β -catenin, retinoic acid, VEGFA, and HIF signaling constitute critical pathways affected [ 15 , 16 ]. Early alterations observed include the inactivation of surfactant proteins and the destruction of organ physiology by cell metaplasia and cell death induction [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…Further vascular development is disturbed by the inflammatory overweight which suppresses HIF-1 α , HIF-2 α , and VEGFA activity [ 15 ]. In the mesenchyme, the inflammatory response dysregulates the central pathways of EGF receptor activity, TGF- β 1-mediated TTG2, PLOD2, and FGF signaling, PDGFR- α -dependent VEGFA action, and myofibroblast and mesenchymal progenitor cell function [ 12 , 16 , 19 – 21 ]. Not surprisingly, dysregulation of myofibroblasts which originate from mesenchymal progenitors and are central drivers of lung development in the saccular stage represents a long-known hallmark of bronchopulmonary dysplasia [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant

Gronbach

Shahzad

Radajewski

et al. 2018

Stem Cells International

Self Cite

View full text Add to dashboard Cite

Preponderance of proinflammatory signals is a characteristic feature of all acute and resulting long-term morbidities of the preterm infant. The proinflammatory actions are best characterized for bronchopulmonary dysplasia (BPD) which is the chronic lung disease of the preterm infant with lifelong restrictions of pulmonary function and severe consequences for psychomotor development and quality of life. Besides BPD, the immature brain, eye, and gut are also exposed to inflammatory injuries provoked by infection, mechanical ventilation, and oxygen toxicity. Despite the tremendous progress in the understanding of disease pathologies, therapeutic interventions with proven efficiency remain restricted to a few drug therapies with restricted therapeutic benefit, partially considerable side effects, and missing option of applicability to the inflamed brain. The therapeutic potential of mesenchymal stromal cells (MSCs)—also known as mesenchymal stem cells—has attracted much attention during the recent years due to their anti-inflammatory activities and their secretion of growth and development-promoting factors. Based on a molecular understanding, this review summarizes the positive actions of exogenous umbilical cord-derived MSCs on the immature lung and brain and the therapeutic potential of reprogramming resident MSCs. The pathomechanistic understanding of MSC actions from the animal model is complemented by the promising results from the first phase I clinical trials testing allogenic MSC transplantation from umbilical cord blood. Despite all the enthusiasm towards this new therapeutic option, the caveats and outstanding issues have to be critically evaluated before a broad introduction of MSC-based therapies.

show abstract

“…Another study demonstrated that neonatal mice receiving mechanical ventilation with oxygen-rich gas (MV-O 2 ) had increased rates of endothelial cell apoptosis, which was aggravated in mice heterozygous (lacking one allele) for the growth factor platelet-derived growth factor receptor alpha (PDGF-Ra). Vascular and alveolar defects were due to reduced PDGF-Ra expression, activation of which supports endothelial survival [51]. Another factor involved in BPD pathophysiology is the monocytic receptor SIGLEC14, which has also been associated with increased risk of COPD exacerbation [52].…”

Section: Early Origins Of Lung Disease: An Interdisciplinary Approachmentioning

confidence: 99%

ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

et al. 2020

View full text Add to dashboard Cite

In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.

show abstract

Attenuated PDGF signaling drives alveolar and microvascular defects in neonatal chronic lung disease

Cited by 38 publications

References 41 publications

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

Targeting miR‐34a/ Pdgfra interactions partially corrects alveologenesis in experimental bronchopulmonary dysplasia

The Potentials and Caveats of Mesenchymal Stromal Cell-Based Therapies in the Preterm Infant

ERS International Congress, Madrid, 2019: highlights from the Basic and Translational Science Assembly

Contact Info

Product

Resources

About