Publications
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Burgess JK, Weiss DJ, Westergren-Thorsson G, et al., 2024, Extracellular matrix as a driver of chronic lung diseases, American Journal of Respiratory Cell and Molecular Biology, Vol: 70, Pages: 239-246, ISSN: 1044-1549
The extracellular matrix (ECM) is not just a 3 dimensional scaffold that provides stable support for all cells in the lungs but is also an important component of chronic fibrotic airways, vascular, and interstitial diseases. It is a bioactive entity that is dynamically modulated during tissue homeostasis and disease, which controls structural and immune cell functions, drug responses, and which can release fragments that have biological activity and that can be used to monitor disease activity. There is a growing recognition of the importance of considering ECM changes in chronic airways, vascular, and interstitial diseases including (i) compositional changes, (ii) structural and organizational changes, and (iii) mechanical changes -and how these impact on disease pathogenesis. Since altered ECM biology is an important component of many lung diseases, disease models must incorporate this factor to fully recapitulate disease-driver pathways and to study potential novel therapeutic interventions. While novel models are evolving that capture some or all of the elements of the altered ECM microenvironment in lung diseases, opportunities exist to more fully understand cell-ECM interactions that will help devise future therapeutic targets to restore function in chronic lung diseases. In this perspective article, we review evolving knowledge about the ECM's role in homeostasis and disease in the lung.
Dean C, cheong S-S, Luis T, et al., 2024, A novel method for floxed gene manipulation using TAT-Cre recombinase in ex vivo precision-cut lung slices (PCLS), Bio-protocol, ISSN: 2331-8325
Kim SY, McTeague D, Cheong S-S, et al., 2024, Deciphering the Impacts of modulating the Wnt-planar cell polarity (PCP) pathway on alveolar repair, Frontiers in Cell and Developmental Biology, Vol: 12, ISSN: 2296-634X
Many adult lung diseases involve dysregulated lung repair. Deciphering the molecular and cellular mechanisms that govern intrinsic lung repair is essential to develop new treatments to repair/regenerate the lungs. Aberrant Wnt signalling is associated with lung diseases including emphysema, idiopathic pulmonary fibrosis and pulmonary arterial hypertension but how Wnt signalling contributes to these diseases is still unclear. There are several alternative pathways that can be stimulated upon Wnt ligand binding, one of these is the Planar Cell Polarity (PCP) pathway which induces actin cytoskeleton remodelling. Wnt5a is known to stimulate the PCP pathway and this ligand is of particular interest in regenerative lung biology because of its association with lung diseases and its role in the alveolar stem cell niche. To decipher the cellular mechanisms through which Wnt5a and the PCP pathway affect alveolar repair we utilised a 3-D ex-vivo model of lung injury and repair, the AIR model. Our results show that Wnt5a specifically enhances the alveolar epithelial progenitor cell population following injury and surprisingly, this function is attenuated but not abolished in Looptail (Lp) mouse lungs in which the PCP pathway is dysfunctional. However, Lp tracheal epithelial cells show reduced stiffness and Lp alveolar epithelial cells are less migratory than wildtype (WT), indicating that Lp lung epithelial cells have a reduced capacity for repair. These findings provide important mechanistic insight into how Wnt5a and the PCP pathway contribute to lung repair and indicate that these components of Wnt signalling may be viable targets for the development of pro-repair treatments.
Cheong S-S, Luis T, Stewart M, et al., 2023, TReATS: a novel method for TAT-Cre recombinase mediated floxed Allele modification in ex vivo tissue slices, Disease Models and Mechanisms, Vol: 16, ISSN: 1754-8403
Precision-Cut Lung Slices (PCLS) are used for a variety of applications. However, methods to manipulate genes in PCLS are currently limited. We developed a novel method, TAT-Cre Recombinase-mediated floxed Allele modification in Tissue Slices (TReATS), to induce highly effective and temporally controlled gene deletion or activation in ex vivo PCLS. Treatment of PCLS from Rosa26-flox-stop-flox-EYFP mice with cell-permeant TAT-Cre recombinase induced ubiquitous EYFP protein expression, indicating successful Cre-mediated excision of the upstream loxP-flanked stop sequence. Quantitative real-time PCR confirmed induction of EYFP. We successfully replicated the TReATS method in PCLS from Vangl2flox/flox mice, leading to the deletion of loxP-flanked exon 4 of the Vangl2 gene. Cre-treated Vangl2flox/flox PCLS exhibited cytoskeletal abnormalities, a known phenotype caused by VANGL2 dysfunction. We report a novel method that by-passes conventional Cre-Lox breeding, allowing rapid and highly effective gene manipulation in ex vivo tissue models.
Dean C, Cheong SS, 2023, Simple Models of Lung Development. In: Magin, C.M. (eds) Engineering Translational Models of Lung Homeostasis and Disease. Advances in Experimental Medicine and Biology, Springer, Cham
Pashiri MT, Portas L, Aung N, et al., 2022, Lung development genes, adult lung function and cardiovascular comorbidities, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Michalaki C, Dean C, Johansson C, 2022, The use of precision-cut lung slices for studying innate immunity to viral infections., Current Protocols, Vol: 2, Pages: e505-e505, ISSN: 2691-1299
Precision-cut lung slices (PCLS) are a novel tool to study cells of the lower airways. As PCLS retain the integrity and architecture of the lung, they constitute a robust model for studying the cells of the lower respiratory tract. Use of PCLS for imaging has been previously documented; however, other applications and techniques can also be applied to PCLS to increase their use and therefore decrease the number of animals needed for each experiment. We present a detailed protocol for generating PCLS from the murine lung. We show that cultured PCLS remain viable up to at least 8 days of culture, that RNA can be isolated from the tissue, and that flow cytometry can be carried out on the cells obtained from the PCLS. Furthermore, we demonstrate that cytokines and chemokines can be detected in the culture supernatants of PCLS exposed to viruses. Overall, these protocols expand the use of PCLS, especially for infection studies. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Precision-cut lung slices (PCLS) Basic Protocol 2: PCLS culture and viability Basic Protocol 3: RNA isolation from PCLS, cDNA conversion, and RT-qPCR Basic Protocol 4: Staining of cells from PCLS for flow cytometry Basic Protocol 5: In vivo RSV administration and ex vivo PCLS RSV exposure.
Ferreira PM, Bayer S, Zhu D, et al., 2022, Extracellular Vesicles in Lung Diseases, EXTRACELLULAR VESICLES, Editors: Chrzanowski, Lim, Kim, Publisher: ROYAL SOC CHEMISTRY, Pages: 216-245, ISBN: 978-1-78801-894-4
Roisin M, Kim SY, Van der Plaat D, et al., 2021, LSC-2021-Investigating the role of vitamin A intake and retinoic acid signalling in lung homeostasis and repair-A multidisciplinary approach, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Juzenaite G, Secklehner J, Vuononvirta J, et al., 2021, Lung marginated and splenic murine resident neutrophils constitute pioneers in tissue-defense during systemic E. coli challenge, Frontiers in Immunology, Vol: 12, Pages: 1-15, ISSN: 1664-3224
The rapid response of neutrophils throughout the body to a systemic challenge is a critical first step in resolution of bacterial infection such as Escherichia coli (E. coli). Here we delineated the dynamics of this response, revealing novel insights into the molecular mechanisms using lung and spleen intravital microscopy and 3D ex vivo culture of living precision cut splenic slices in combination with fluorescent labelling of endogenous leukocytes. Within seconds after challenge, intravascular marginated neutrophils and lung endothelial cells (ECs) work cooperatively to capture pathogens. Neutrophils retained on lung ECs slow their velocity and aggregate in clusters that enlarge as circulating neutrophils carrying E. coli stop within the microvasculature. The absolute number of splenic neutrophils does not change following challenge; however, neutrophils increase their velocity, migrate to the marginal zone (MZ) and form clusters. Irrespective of their location all neutrophils capturing heat-inactivated E. coli take on an activated phenotype showing increasing surface CD11b. At a molecular level we show that neutralization of ICAM-1 results in splenic neutrophil redistribution to the MZ under homeostasis. Following challenge, splenic levels of CXCL12 and ICAM-1 are reduced allowing neutrophils to migrate to the MZ in a CD29-integrin dependent manner, where the enlargement of splenic neutrophil clusters is CXCR2-CXCL2 dependent. We show directly molecular mechanisms that allow tissue resident neutrophils to provide the first lines of antimicrobial defense by capturing circulating E. coli and forming clusters both in the microvessels of the lung and in the parenchyma of the spleen.
Papakrivopoulou E, Jafree DJ, Dean CH, et al., 2021, The biological significance and implications of planar cell polarity for nephrology, Frontiers in Physiology, Vol: 12, ISSN: 1664-042X
The orientation of cells in two-dimensional and three-dimensional space underpins how the kidney develops and responds to disease. The process by which cells orientate themselves within the plane of a tissue is termed planar cell polarity. In this Review, we discuss how planar cell polarity and the proteins that underpin it govern kidney organogenesis and pathology. The importance of planar cell polarity and its constituent proteins in multiple facets of kidney development is emphasised, including ureteric bud branching, tubular morphogenesis and nephron maturation. An overview is given of the relevance of planar cell polarity and its proteins for inherited human renal diseases, including congenital malformations with unknown aetiology and polycystic kidney disease. Finally, recent work is described outlining the influence of planar cell polarity proteins on glomerular diseases and highlight how this fundamental pathway could yield a new treatment paradigm for nephrology.
Kim SY, Mongey S, Wang P, et al., 2021, The Acid Injury and Repair (AIR) model: A new ex vivo tool to understand lung repair, Biomaterials, Vol: 267, ISSN: 0142-9612
Research into mechanisms underlying lung injury and subsequent repair responses is currently of paramount importance. There is a paucity of models that bridge the gap between in vitro and in vivo research. Such intermediate models are critical for researchers to decipher the mechanisms that drive repair and to test potential new treatments for lung repair and regeneration. Here we report the establishment of a new tool, the Acid Injury and Repair (AIR) model, that will facilitate studies of lung tissue repair. In this model, injury is applied to a restricted area of a precision-cut lung slice using hydrochloric acid, a clinically relevant driver. The surrounding area remains uninjured, thus mimicking the heterogeneous pattern of injury frequently observed in lung diseases. We show that in response to injury, the percentage of progenitor cells (pro surfactant protein C, proSP-C and TM4SF1 positive) significantly increases in the injured region. Whereas in the uninjured area, the percentage of proSP-C/TM4SF1 cells remains unchanged but proliferating cells (Ki67 positive) increase. These effects are modified in the presence of inhibitors of proliferation (Cytochalasin D) and Wnt secretion (C59) demonstrating that the AIR model is an important new tool for research into lung disease pathogenesis and potential regenerative medicine strategies.
Kim S, Mongey R, Griffiths M, et al., 2020, An ex vivo acid injury and repair (AIR) model using precision-cut lung slices to understand lung injury and repair, Current protocols in mouse biology, Vol: 10, Pages: e85-e85, ISSN: 2161-2617
Recent advances in cell culture models like air‒liquid interface culture and ex vivo models such as organoids have advanced studies of lung biology; however, gaps exist between these models and tools that represent the complexity of the three‐dimensional environment of the lung. Precision‐cut lung slices (PCLS) mimic the in vivo environment and bridge the gap between in vitro and in vivo models. We have established the acid injury and repair (AIR) model where a spatially restricted area of tissue is injured using drops of HCl combined with Pluronic gel. Injury and repair are assessed by immunofluorescence using robust markers, including Ki67 for cell proliferation and prosurfactant protein C for alveolar type 2/progenitor cells. Importantly, the AIR model enables the study of injury and repair in mouse lung tissue without the need for an initial in vivo injury, and the results are highly reproducible. Here, we present detailed protocols for the generation of PCLS and the AIR model. We also describe methods to analyze and quantify injury in AIR‐PCLS by immunostaining with established early repair markers and fluorescence imaging. This novel ex vivo model is a versatile tool for studying lung cell biology in acute lung injury and for semi‐high‐throughput screening of potential therapeutics. © 2020 Wiley Periodicals LLC.
Cheong SS, Akram K, Metellan C, et al., 2020, The planar polarity component Vangl2 is a key regulator of mechanosignaling, Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X
VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The Vangl2Lp mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from Vangl2Lp/+ mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. Vangl2Lp/+ tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in Vangl2Lp/+ TECs. YAP signaling in Vangl2Lp airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in Vangl2Lp/+, confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.
Dean C, Taylor B, Rice A, et al., 2020, Mechanism of lung development in the aetiology of adult congenital pulmonary airway malformations, Thorax, Vol: 75, Pages: 1001-1003, ISSN: 0040-6376
Congenital pulmonary airway malformations (CPAMs) are rare lung abnormalities that result in cyst formation and are associated with respiratory distress in infants and malignant potential in adults. The pathogenesis of CPAMs remains unknown but data suggest disruption of the normal proximo-distal programme of airway branching and differentiation. Here, we demonstrate that adult human CPAM are lined with epithelium that retains SOX-2 and thyroid transcription factor-1 immunohistochemical markers, characteristic of the developing lung. However, RALDH-1, another key marker, is absent. This suggests a more complex aetiology for CPAM than complete focal arrest of lung development and may provide insight to the associated risk of malignancy.
Portas L, Pereira M, Shaheen SO, et al., 2020, Lung development genes and adult lung function, American Journal of Respiratory and Critical Care Medicine, Vol: 202, Pages: 853-865, ISSN: 1073-449X
RATIONALE: Poor lung health in adult life may occur partly through suboptimal growth and development, as suggested by epidemiological evidence pointing to early life risk factors. OBJECTIVES: To systematically investigate the effects of lung development genes on adult lung function. METHODS: Using UK Biobank data, we tested the association of 391 genes known to influence lung development with FVC and FEV1/FVC. We split the dataset into two random subsets of 207,616 and 138,411 individuals, using the larger to select the most promising signals and the smaller for replication. MEASUREMENTS AND MAIN RESULTS: We identified 55 genes, of which 36 (16 for FVC; 19 for FEV1/FVC; 1 for both) had not been identified in the largest, most recent genome-wide study of lung function. Most of these 36 signals were intronic variants; expression data from blood and lung tissue showed that the majority affect the expression of the genes they lie within. Further testing of 34 of these 36 signals in the CHARGE and SpiroMeta consortia showed that 16 replicated after Bonferroni correction and another 12 at nominal significance level. 53 of the 55 genes fell into four biological categories whose function is to regulate organ size and cell integrity (growth factors; transcriptional regulators; cell-cell adhesion; extra-cellular matrix), suggesting that these specific processes are important for adult lung health. CONCLUSIONS: Our study demonstrates the importance of lung development genes in regulating adult lung function and influencing both restrictive and obstructive patterns. Further investigation of these developmental pathways could lead to druggable targets.
Rao-Bhatia A, Zhu M, Yin W-C, et al., 2020, Hedgehog-activated fat4 and PCP pathways mediate mesenchymal cell clustering and villus formation in gut development, Developmental Cell, Vol: 52, Pages: 647-658.e6, ISSN: 1534-5807
During development, intestinal epithelia undergo dramatic morphogenesis mediated by mesenchymal signaling to form villi, which are required for efficient nutrient absorption and host defense. Although both smooth-muscle-induced physical forces and mesenchymal cell clustering beneath emerging villi are implicated in epithelial folding, the underlying cellular mechanisms are unclear. Hedgehog (Hh) signaling can mediate both processes. We therefore analyzed its direct targetome and revealed GLI2 transcriptional activation of atypical cadherin and planar cell polarity (PCP) genes. By examining Fat4 and Dchs1 knockout mice, we demonstrate their critical roles in villus formation. Analyses of PCP-mutant mice and genetic interaction studies show that the Fat4-Dchs1 axis acts in parallel to the core-Vangl2 PCP axis to control mesenchymal cell clustering. Moreover, live light-sheet fluorescence microscopy and cultured PDGFRα+ cells reveal a requirement for PCP in their oriented cell migration guided by WNT5A. Therefore, mesenchymal PCP induced by Hh signaling drives cell clustering and subsequent epithelial remodeling.
Wilson DH, Jarman EJ, Mellin RP, et al., 2020, Non-canonical Wnt signalling regulates scarring in biliary disease via the planar cell polarity receptors, Nature Communications, Vol: 11, Pages: 1-13, ISSN: 2041-1723
The number of patients diagnosed with chronic bile duct disease is increasing and in most cases these diseases result in chronic ductular scarring, necessitating liver transplantation. The formation of ductular scaring affects liver function; however, scar-generating portal fibroblasts also provide important instructive signals to promote the proliferation and differentiation of biliary epithelial cells. Therefore, understanding whether we can reduce scar formation while maintaining a pro-regenerative microenvironment will be essential in developing treatments for biliary disease. Here, we describe how regenerating biliary epithelial cells express Wnt-Planar Cell Polarity signalling components following bile duct injury and promote the formation of ductular scars by upregulating pro-fibrogenic cytokines and positively regulating collagen-deposition. Inhibiting the production of Wnt-ligands reduces the amount of scar formed around the bile duct, without reducing the development of the pro-regenerative microenvironment required for ductular regeneration, demonstrating that scarring and regeneration can be uncoupled in adult biliary disease and regeneration.
Akram K, Yates L, Mongey R, et al., 2019, Time-lapse imaging of alveologenesis in mouse precision-cut lung slices, Bio-protocol, Vol: 9, ISSN: 2331-8325
Alveoli are the gas-exchange units of lung. The process of alveolar development,alveologenesis, is regulated by a complex network of signaling pathways that act on various cell typesincluding alveolar type I and II epithelial cells, fibroblasts and the vascular endothelium. Dysregulatedalveologenesis results in bronchopulmonary dysplasia in neonates and in adults, disrupted alveolarregeneration is associated with chronic lung diseases including COPD and pulmonary fibrosis.Therefore, visualizing alveologenesis is critical to understand lung homeostasis and for thedevelopment of effective therapies for incurable lung diseases. We have developed a technique tovisualize alveologenesis in real-time using a combination of widefield microscopy and imagedeconvolution of precision-cut lung slices. Here, we describe this live imaging technique in step-by-stepdetail. This time-lapse imaging technique can be used to capture the dynamics of individual cells withintissue slices over a long time period (up to 16 h), with minimal loss of fluorescence or cell toxicity.
Kim SY, Mongey R, Wang P, et al., 2019, LSC-2019-A novel ex-vivo approach to study lung injury and repair, European-Respiratory-Society (ERS) International Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Ng-Blichfeldt J-P, Gosens R, Dean C, et al., 2019, Regenerative pharmacology for COPD: breathing new life into old lungs, Thorax, Vol: 74, Pages: 890-897, ISSN: 1468-3296
Chronic obstructive pulmonary disease (COPD) is a major global health concern with few effective treatments. Widespread destruction of alveolar tissue contributes to impaired gas exchange in severe COPD, and recent radiological evidence suggests that destruction of small airways is a major contributor to increased peripheral airway resistance in disease. This important finding might in part explain the failure of conventional anti-inflammatory treatments to restore lung function even in patients with mild disease. There is a clear need for alternative pharmacological strategies for patients with COPD/emphysema. Proposed regenerative strategies such as cell therapy and tissue engineering are hampered by poor availability of exogenous stem cells, discouraging trial results, and risks and cost associated with surgery. An alternative therapeutic approach is augmentation of lung regeneration and/or repair by biologically active factors, which have potential to be employed on a large scale. In favour of this strategy, the healthy adult lung is known to possess a remarkable endogenous regenerative capacity. Numerous preclinical studies have shown induction of regeneration in animal models of COPD/emphysema. Here, we argue that given the widespread and irreversible nature of COPD, serious consideration of regenerative pharmacology is necessary. However, for this approach to be feasible, a better understanding of the cell-specific molecular control of regeneration, the regenerative potential of the human lung and regenerative competencies of patients with COPD are required.
Dean C, Cheong SS, 2019, On the move: the commander IL-4 leads the cell army in collective migration, American Journal of Respiratory Cell and Molecular Biology, Vol: 60, Pages: 377-378, ISSN: 1044-1549
Taylor BA, Hind M, Rice A, et al., 2019, Investigating the Molecular Mechanisms of Congenital Pulmonary Airway Malformation (CPAM), 211th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S11-S11, ISSN: 0022-3417
Akram K, Yates L, Mongey R, et al., 2019, Live imaging of alveologenesis in precision-cut lung slices reveals dynamic epithelial cell behaviour, Nature Communications, Vol: 10, Pages: 1-16, ISSN: 2041-1723
Damage to alveoli, the gas-exchanging region of the lungs, is a component of many chronic and acute lung diseases. In addition, insufficient generation of alveoli results in bronchopulmonary dysplasia, a disease of prematurity. Therefore visualising the process of alveolar development (alveologenesis) is critical for our understanding of lung homeostasis and for the development of treatments to repair and regenerate lung tissue. Using long-term, time-lapse imaging of precision-cut lung slices, we show alveologenesis for the first time. We reveal that during this process, epithelial cells are highly mobile and we identify specific cell behaviours that contribute to alveologenesis: cell clustering, hollowing and cell extension. Using the cytoskeleton inhibitors blebbistatin and cytochalasin D, we showed that cell migration is a key driver of alveologenesis. This study reveals important novel information about lung biology and provides a new system in which to manipulate alveologenesis genetically and pharmacologically.
Henderson DJ, Long DA, Dean CH, 2018, Planar cell polarity in organ formation, Current Opinion in Cell Biology, Vol: 55, Pages: 96-103, ISSN: 0955-0674
The planar cell polarity (PCP) pathway controls a variety of morphological events across many species. During embryonic development, the PCP pathway regulates coordinated behaviour of groups of cells to direct morphogenetic processes such as convergent extension and collective cell migration. In this review we discuss the increasingly prominent role of the PCP pathway in organogenesis, focusing on the lungs, kidneys and heart. We also highlight emerging evidence that PCP gene mutations are associated with adult diseases.
Dean CH, Snelgrove RJ, 2018, New rules for club development: new insights into human small airway epithelial club cell ontogeny and function, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1355-1366, ISSN: 1073-449X
Dean C, Papakrivopoulou E, Vasilopoulou E, et al., 2018, Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury, Journal of Pathology, Vol: 246, Pages: 485-496, ISSN: 0022-3417
Planar cell polarity (PCP) pathways control the orientation and alignment of epithelial cells within tissues. Van Gogh‐like 2 (Vangl2) is a key PCP protein that is required for normal differentiation of kidney glomeruli and tubules. Vangl2 has also been implicated in modifying the course of acquired glomerular disease and here we further explored how Vangl2 impacts on glomerular pathobiology in this context. Targeted genetic deletion of Vangl2 in mouse glomerular epithelial podocytes enhanced the severity of not only irreversible accelerated nephrotoxic nephritis but also lipopolysaccharide‐induced reversible glomerular damage. In each proteinuric model, genetic deletion of Vangl2 in podocytes was associated with an increased ratio of active‐MMP9 to inactive MMP9, an enzyme involved in tissue remodelling. Additionally, by interrogating microarray data from two cohorts of renal patients, we report increased VANGL2 transcript levels in glomeruli of individuals with focal segmental glomerulosclerosis, suggesting that the molecule may also be involved in certain human glomerular diseases. These observations support the conclusion that Vangl2 modulates glomerular injury, at least in part by acting as a brake on MMP9, a potentially harmful endogenous enzyme.
Zhang Y, Poobalasingam T, Yates LL, et al., 2018, Manipulation of Dipeptidylpeptidase 10 in mouse and human in vivo and in vitro models indicates a protective role in asthma, Disease Models and Mechanisms, Vol: 11, ISSN: 1754-8403
We previously identified dipeptidylpeptidase 10 (DPP10) on chromosome 2 as a human asthma susceptibility gene, through positional cloning. Initial association results were confirmed in many subsequent association studies but the functional role of DPP10 in asthma remains unclear. Using the MRC Harwell N-ethyl-N-nitrosourea (ENU) DNA archive, we identified a point mutation in Dpp10 that caused an amino acid change from valine to aspartic acid in the β-propeller region of the protein. Mice carrying this point mutation were recovered and a congenic line was established (Dpp10145D). Macroscopic examination and lung histology revealed no significant differences between wild-type and Dpp10145D/145D mice. However, after house dust mite (HDM) treatment, Dpp10 mutant mice showed significantly increased airway resistance in response to 100 mg/ml methacholine. Total serum IgE levels and bronchoalveolar lavage (BAL) eosinophil counts were significantly higher in homozygotes than in control mice after HDM treatment. DPP10 protein is present in airway epithelial cells and altered expression is observed in both tissue from asthmatic patients and in mice following HDM challenge. Moreover, knockdown of DPP10 in human airway epithelial cells results in altered cytokine responses. These results show that a Dpp10 point mutation leads to increased airway responsiveness following allergen challenge and provide biological evidence to support previous findings from human genetic studies.
Alcada J, Shao D, Griffiths MJ, et al., 2018, Retinoic Acid Upregulates Endothelial-Derived Angiocrine Factors to Promote Human Alveolar Epithelial Repair, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Alcada J, Shao DS, Griffiths MJD, et al., 2017, MECHANISMS OF REGENERATION: RETINOIC ACID ACTS VIA THE ENDOTHELIUM TO DRIVE HUMAN LUNG REPAIR, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A106-A107, ISSN: 0040-6376
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