| 1. |
- Alsafadi, Hani N, et al.
(författare)
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Applications and Approaches for Three-Dimensional Precision-Cut Lung Slices. Disease Modeling and Drug Discovery
- 2020
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549. ; 62:6, s. 681-691
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Forskningsöversikt (refereegranskat)abstract
- Chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease, interstitial lung disease, and lung cancer, are among the leading causes of morbidity globally and impose major health and financial burdens on patients and society. Effective treatments are scarce, and relevant human model systems to effectively study CLD pathomechanisms and thus discover and validate potential new targets and therapies are needed. Precision-cut lung slices (PCLS) from healthy and diseased human tissue represent one promising tool that can closely recapitulate the complexity of the lung's native environment, and recently, improved methodologies and accessibility to human tissue have led to an increased use of PCLS in CLD research. Here, we discuss approaches that use human PCLS to advance our understanding of CLD development, as well as drug discovery and validation for CLDs. PCLS enable investigators to study complex interactions among different cell types and the extracellular matrix in the native three-dimensional architecture of the lung. PCLS further allow for high-resolution (live) imaging of cellular functions in several dimensions. Importantly, PCLS can be derived from diseased lung tissue upon lung surgery or transplantation, thus allowing the study of CLDs in living human tissue. Moreover, CLDs can be modeled in PCLS derived from normal lung tissue to mimic the onset and progression of CLDs, complementing studies in end-stage diseased tissue. Altogether, PCLS are emerging as a remarkable tool to further bridge the gap between target identification and translation into clinical studies, and thus open novel avenues for future precision medicine approaches.
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| 2. |
- Ryan, Amy L, et al.
(författare)
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Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases 2017 : An Official American Thoracic Society Workshop Report
- 2019. - 4
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The University of Vermont Larner College of Medicine, in collaboration with the National Heart, Lung, and Blood Institute (NHLBI), the Alpha-1 Foundation, the American Thoracic Society, the Cystic Fibrosis Foundation, the European Respiratory Society, the International Society for Cell & Gene Therapy, and the Pulmonary Fibrosis Foundation, convened a workshop titled "Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases" from July 24 through 27, 2017, at the University of Vermont, Burlington, Vermont. The conference objectives were to review and discuss current understanding of the following topics: 1) stem and progenitor cell biology and the role that they play in endogenous repair or as cell therapies after lung injury, 2) the emerging role of extracellular vesicles as potential therapies, 3) ex vivo bioengineering of lung and airway tissue, and 4) progress in induced pluripotent stem cell protocols for deriving lung cell types and applications in disease modeling. All of these topics are research areas in which significant and exciting progress has been made over the past few years. In addition, issues surrounding the ethics and regulation of cell therapies worldwide were discussed, with a special emphasis on combating the growing problem of unproven cell interventions being administered to patients with lung diseases. Finally, future research directions were discussed, and opportunities for both basic and translational research were identified.
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| 3. |
- Wrenn, Sean M, et al.
(författare)
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Avian lungs : A novel scaffold for lung bioengineering
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:6, s. 0198956-0198956
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Tidskriftsartikel (refereegranskat)abstract
- Allogeneic lung transplant is limited both by the shortage of available donor lungs and by the lack of suitable long-term lung assist devices to bridge patients to lung transplantation. Avian lungs have different structure and mechanics resulting in more efficient gas exchange than mammalian lungs. Decellularized avian lungs, recellularized with human lung cells, could therefore provide a powerful novel gas exchange unit for potential use in pulmonary therapeutics. To initially assess this in both small and large avian lung models, chicken (Gallus gallus domesticus) and emu (Dromaius novaehollandiae) lungs were decellularized using modifications of a detergent-based protocol, previously utilized with mammalian lungs. Light and electron microscopy, vascular and airway resistance, quantitation and gel analyses of residual DNA, and immunohistochemical and mass spectrometric analyses of remaining extracellular matrix (ECM) proteins demonstrated maintenance of lung structure, minimal residual DNA, and retention of major ECM proteins in the decellularized scaffolds. Seeding with human bronchial epithelial cells, human pulmonary vascular endothelial cells, human mesenchymal stromal cells, and human lung fibroblasts demonstrated initial cell attachment on decellularized avian lungs and growth over a 7-day period. These initial studies demonstrate that decellularized avian lungs may be a feasible approach for generating functional lung tissue for clinical therapeutics.
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| 4. |
- Cuevas Ocaña, Sara, et al.
(författare)
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ERS International Congress 2022 : highlights from the Basic and Translational Science Assembly
- 2023
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Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 9:2
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Forskningsöversikt (refereegranskat)abstract
- In this review, the Basic and Translational Science Assembly of the European Respiratory Society provides an overview of the 2022 International Congress highlights. We discuss the consequences of respiratory events from birth until old age regarding climate change related alterations in air quality due to pollution caused by increased ozone, pollen, wildfires and fuel combustion as well as the increasing presence of microplastic and microfibres. Early life events such as the effect of hyperoxia in the context of bronchopulmonary dysplasia and crucial effects of the intrauterine environment in the context of pre-eclampsia were discussed. The Human Lung Cell Atlas (HLCA) was put forward as a new point of reference for healthy human lungs. The combination of single-cell RNA sequencing and spatial data in the HLCA has enabled the discovery of new cell types/states and niches, and served as a platform that facilitates further investigation of mechanistic perturbations. The role of cell death modalities in regulating the onset and progression of chronic lung diseases and its potential as a therapeutic target was also discussed. Translational studies identified novel therapeutic targets and immunoregulatory mechanisms in asthma. Lastly, it was highlighted that the choice of regenerative therapy depends on disease severity, ranging from transplantation to cell therapies and regenerative pharmacology.
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| 5. |
- De Santis, Martina M, et al.
(författare)
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Extracellular-Matrix-Reinforced Bioinks for 3D Bioprinting Human Tissue
- 2021
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Ingår i: Advanced Materials. - : Wiley. - 1521-4095 .- 0935-9648. ; 33:3
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Tidskriftsartikel (refereegranskat)abstract
- Recent advances in 3D bioprinting allow for generating intricate structures with dimensions relevant for human tissue, but suitable bioinks for producing translationally relevant tissue with complex geometries remain unidentified. Here, a tissue-specific hybrid bioink is described, composed of a natural polymer, alginate, reinforced with extracellular matrix derived from decellularized tissue (rECM). rECM has rheological and gelation properties beneficial for 3D bioprinting while retaining biologically inductive properties supporting tissue maturation ex vivo and in vivo. These bioinks are shear thinning, resist cell sedimentation, improve viability of multiple cell types, and enhance mechanical stability in hydrogels derived from them. 3D printed constructs generated from rECM bioinks suppress the foreign body response, are pro-angiogenic and support recipient-derived de novo blood vessel formation across the entire graft thickness in a murine model of transplant immunosuppression. Their proof-of-principle for generating human tissue is demonstrated by 3D bioprinting human airways composed of regionally specified primary human airway epithelial progenitor and smooth muscle cells. Airway lumens remained patent with viable cells for one month in vitro with evidence of differentiation into mature epithelial cell types found in native human airways. rECM bioinks are a promising new approach for generating functional human tissue using 3D bioprinting.
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| 6. |
- Gilpin, Sarah E., et al.
(författare)
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Acellular human lung scaffolds to model lung disease and tissue regeneration
- 2018
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Ingår i: European Respiratory Review. - : European Respiratory Society (ERS). - 0905-9180 .- 1600-0617. ; 27:148
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Forskningsöversikt (refereegranskat)abstract
- Recent advances in whole lung bioengineering have opened new doors for studying lung repair and regeneration ex vivo using acellular human derived lung tissue scaffolds. Methods to decellularise whole human lungs, lobes or resected segments from normal and diseased human lungs have been developed using both perfusion and immersion based techniques. Immersion based techniques allow laboratories without access to intact lobes the ability to generate acellular human lung scaffolds. Acellular human lung scaffolds can be further processed into small segments, thin slices or extracellular matrix extracts, to study cell behaviour such as viability, proliferation, migration and differentiation. Recent studies have offered important proof of concept of generating sufficient primary endothelial and lung epithelial cells to recellularise whole lobes that can be maintained for several days ex vivo in a bioreactor to study regeneration. In parallel, acellular human lung scaffolds have been increasingly used for studying cell-extracellular environment interactions. These studies have helped provide new insights into the role of the matrix and the extracellular environment in chronic human lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Acellular human lung scaffolds are a versatile new tool for studying human lung repair and regeneration ex vivo.
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| 7. |
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| 8. |
- Wagner, Darcy E, et al.
(författare)
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Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019
- 2020
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Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 6:4
-
Forskningsöversikt (refereegranskat)abstract
- A workshop entitled "Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases" was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology.
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| 9. |
- Alsafadi, Hani N, et al.
(författare)
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Simultaneous isolation of proximal and distal lung progenitor cells from individual mice using a 3D printed guide reduces proximal cell contamination of distal lung epithelial cell isolations
- 2022
-
Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 17:12, s. 2718-2731
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Tidskriftsartikel (refereegranskat)abstract
- The respiratory epithelium consists of multiple, functionally distinct cell types and is maintained by regionally specific progenitor populations that repair the epithelium following injury. Several in vitro methods exist for studying lung epithelial repair using primary murine lung cells, but isolation methods are hampered by a lack of surface markers distinguishing epithelial progenitors along the respiratory epithelium. Here, we developed a 3D printed lobe divider (3DLD) to aid in simultaneous isolation of proximal versus distal lung epithelial progenitors from individual mice that give rise to differentiated epithelia in multiple in vitro assays. In contrast to 3DLD-isolated distal progenitor cells, commonly used manual tracheal ligation methods followed by lobe removal resulted in co-isolation of rare proximal cells with distal cells, which altered the transcriptional landscape and size distribution of distal organoids. The 3DLD aids in reproducible isolation of distal versus proximal progenitor populations and minimizes the potential for contaminating populations to confound in vitro assays.
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| 10. |
- Broberg, Ellen, et al.
(författare)
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Particle Flow Profiles From the Airways Measured by PExA Differ in Lung Transplant Recipients Who Develop Primary Graft Dysfunction
- 2019
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Ingår i: Experimental and clinical transplantation. - : Baskent University. - 1304-0855 .- 2146-8427. ; 17:6, s. 803-812
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Primary graft dysfunction is a severe form of acute lung injury and a major cause of early morbidity and mortality encountered after lung transplant.We used a customized PExA 2.0 instrument (PExA, Gothenburg, Sweden) to measure particle flow in exhaled air during mechanical ventilation in the intensive care unit. Our objective was to discover whether patients who developed primary graft dysfunction had different particle flow patterns from the airways. We used volume-controlled ventilation and pressure-controlled ventilation to see whether changes in particle patterns could be observed in both mechanical ventilation settings.MATERIALS AND METHODS: First, we investigated whether it was safe to use a customized PExA 2.0 in conjunction with mechanical ventilation. Next, 12 lung transplant patients were randomized to either daily volumecontrolled ventilation or pressure-controlled ventilation as the first mode of treatment until extubation.RESULTS: In our study group, 6 patients did not develop primary graft dysfunction and 6 developed primary graft dysfunction. Patients with primary graft dysfunction underwent mechanical ventilation significantly longer; they also showed a stepwise increase in particle count from day 0 until extubation. We observed no adverse events related to the PExA 2.0 device.CONCLUSIONS: This study suggests that the PExA 2.0 device is safe to use in conjunction with mechanical ventilation in the intensive care unit. Lung transplant patients who developed primary graft dysfunction showed a different particle profile from the airways before clinical signs of primary graft dysfunction developed. Online assessment of ventilation impact before presentation of tissue changes may allow realtime detection of primary graft dysfunction, thus preventing or reducing its effects.
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| 11. |
- Bölükbas, Deniz A., et al.
(författare)
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The Preparation of Decellularized Mouse Lung Matrix Scaffolds for Analysis of Lung Regenerative Cell Potential
- 2019
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1940, s. 275-295
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Tidskriftsartikel (refereegranskat)abstract
- Lung transplantation is the only option for patients with end-stage lung disease, but there is a shortage of available lung donors. Furthermore, efficiency of lung transplantation has been limited due to primary graft dysfunction. Recent mouse models mimicking lung disease in humans have allowed for deepening our understanding of disease pathomechanisms. Moreover, new techniques such as decellularization and recellularization have opened up new possibilities to contribute to our understanding of the regenerative mechanisms involved in the lung. Stripping the lung of its native cells allows for unprecedented analyses of extracellular matrix and sets a physiologic platform to study the regenerative potential of seeded cells. A comprehensive understanding of the molecular pathways involved for lung development and regeneration in mouse models can be translated to regeneration strategies in higher organisms, including humans. Here we describe and discuss several techniques used for murine lung de- and recellularization, methods for evaluation of efficacy including histology, protein/RNA isolation at the whole lung, as well as lung slices level.
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| 12. |
- Bölükbas, Deniz, et al.
(författare)
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Organ-Restricted Vascular Delivery of Nanoparticles for Lung Cancer Therapy
- 2020
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Ingår i: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 3:7
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Tidskriftsartikel (refereegranskat)abstract
- Nanoparticle-based targeted drug delivery holds promise for treatment of cancers. However, most approaches fail to be translated into clinical success due to ineffective tumor targeting in vivo. Here, the delivery potential of mesoporous silica nanoparticles (MSN) functionalized with targeting ligands for epidermal growth factor receptor and C─C chemokine receptor type 2 is explored in lung tumors. The addition of active targeting ligands on MSNs enhances their uptake in vitro but fails to promote specific delivery to tumors in vivo, when administered systemically via the blood or locally to the lung into immunocompetent murine lung cancer models. Ineffective tumor targeting is due to efficient clearance of the MSNs by the phagocytic cells of the liver, spleen, and lung. These limitations, however, are successfully overcome using a novel organ-restricted vascular delivery (ORVD) approach. ORVD in isolated and perfused mouse lungs of Kras-mutant mice enables effective nanoparticle extravasation from the tumor vasculature into the core of solid lung tumors. In this study, ORVD promotes tumor cell-specific uptake of nanoparticles at cellular resolution independent of their functionalization with targeting ligands. Organ-restricted vascular delivery thus opens new avenues for optimized nanoparticles for lung cancer therapy and may have broad applications for other vascularized tumor types.
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| 13. |
- Conlon, Thomas M, et al.
(författare)
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Inhibition of LTβR signalling activates WNT-induced regeneration in lung
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588:7836, s. 151-156
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Tidskriftsartikel (refereegranskat)abstract
- Lymphotoxin β-receptor (LTβR) signalling promotes lymphoid neogenesis and the development of tertiary lymphoid structures1,2, which are associated with severe chronic inflammatory diseases that span several organ systems3-6. How LTβR signalling drives chronic tissue damage particularly in the lung, the mechanism(s) that regulate this process, and whether LTβR blockade might be of therapeutic value have remained unclear. Here we demonstrate increased expression of LTβR ligands in adaptive and innate immune cells, enhanced non-canonical NF-κB signalling, and enriched LTβR target gene expression in lung epithelial cells from patients with smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke. Therapeutic inhibition of LTβR signalling in young and aged mice disrupted smoking-related inducible bronchus-associated lymphoid tissue, induced regeneration of lung tissue, and reverted airway fibrosis and systemic muscle wasting. Mechanistically, blockade of LTβR signalling dampened epithelial non-canonical activation of NF-κB, reduced TGFβ signalling in airways, and induced regeneration by preventing epithelial cell death and activating WNT/β-catenin signalling in alveolar epithelial progenitor cells. These findings suggest that inhibition of LTβR signalling represents a viable therapeutic option that combines prevention of tertiary lymphoid structures1 and inhibition of apoptosis with tissue-regenerative strategies.
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| 14. |
- Costa, Rita, et al.
(författare)
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A drug screen with approved compounds identifies amlexanox as a novel Wnt/β-catenin activator inducing lung epithelial organoid formation
- 2021
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 178:19, s. 4026-4041
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose: Emphysema is an incurable disease characterized by loss of lung tissue leading to impaired gas exchange. Wnt/β-catenin signalling is reduced in emphysema, and exogenous activation of the pathway in experimental models in vivo and in human ex vivo lung tissue improves lung function and structure. We sought to identify a pharmaceutical able to activate Wnt/β-catenin signalling and assess its potential to activate lung epithelial cells and repair. Experimental Approach: We screened 1216 human-approved compounds for Wnt/β-catenin signalling activation using luciferase reporter cells and selected candidates based on their computationally predicted protein targets. We further performed confirmatory luciferase reporter and metabolic activity assays. Finally, we studied the regenerative potential in murine adult epithelial cell-derived lung organoids and in vivo using a murine elastase-induced emphysema model. Key Results: The primary screen identified 16 compounds that significantly induced Wnt/β-catenin-dependent luciferase activity. Selected compounds activated Wnt/β-catenin signalling without inducing cell toxicity or proliferation. Two compounds were able to promote organoid formation, which was reversed by pharmacological Wnt/β-catenin inhibition, confirming the Wnt/β-catenin-dependent mechanism of action. Amlexanox was used for in vivo evaluation, and preventive treatment resulted in improved lung function and structure in emphysematous mouse lungs. Moreover, gene expression of Hgf, an important alveolar repair marker, was increased, whereas disease marker Eln was decreased, indicating that amlexanox induces pro-regenerative signalling in emphysema. Conclusion and Implications: Using a drug screen based on Wnt/β-catenin activity, organoid assays and a murine emphysema model, amlexanox was identified as a novel potential therapeutic agent for emphysema.
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| 15. |
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| 16. |
- De Santis, Martina M, et al.
(författare)
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How to build a lung : latest advances and emerging themes in lung bioengineering
- 2018
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 52, s. 1-19
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Forskningsöversikt (refereegranskat)abstract
- Chronic respiratory diseases remain a major cause of morbidity and mortality worldwide. The only option at end-stage disease is lung transplantation, but there are not enough donor lungs to meet clinical demand. Alternative options to increase tissue availability for lung transplantation are urgently required to close the gap on this unmet clinical need. A growing number of tissue engineering approaches are exploring the potential to generate lung tissue ex vivo for transplantation. Both biologically derived and manufactured scaffolds seeded with cells and grown ex vivo have been explored in pre-clinical studies, with the eventual goal of generating functional pulmonary tissue for transplantation. Recently, there have been significant efforts to scale-up cell culture methods to generate adequate cell numbers for human-scale bioengineering approaches. Concomitantly, there have been exciting efforts in designing bioreactors that allow for appropriate cell seeding and development of functional lung tissue over time. This review aims to present the current state-of-the-art progress for each of these areas and to discuss promising new ideas within the field of lung bioengineering.
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| 17. |
- De Santis, Martina M., et al.
(författare)
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Lung tissue bioengineering for transplantation and modelling of development, disease and regeneration
- 2021
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Ingår i: ERS Monograph. - 2312-508X. ; 2021:91, s. 248-272
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Tidskriftsartikel (refereegranskat)abstract
- The lung is a vital and dynamic organ that serves as a critical first barrier to environmental stimuli and facilitates gas exchange from birth until death. Developmental or genetic defects that impair lung function severely impact quality of life. Minor defects present in early life increase the likelihood that patients will develop chronic lung diseases in adulthood that have no cure. Current therapies aim to slow disease progression, with lung transplantation remaining the only option at end-stage disease. While a number of discoveries have been made using conventional cell culture and in vivo animal studies, new approaches are needed to develop effective therapies. Recent advances using bioengineering have created new models that more closely recapitulate human development and disease. In parallel, progress has been made towards generating lung tissue in the laboratory with the ultimate aim of transplantation. This chapter covers the progress and recent advances in applying bioengineering approaches towards improving our understanding of lung development, disease and regeneration.
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| 18. |
- Doryab, Ali, et al.
(författare)
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A Biomimetic, Copolymeric Membrane for Cell-Stretch Experiments with Pulmonary Epithelial Cells at the Air-Liquid Interface
- 2021
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Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028. ; 31:10
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Tidskriftsartikel (refereegranskat)abstract
- Chronic respiratory diseases are among the leading causes of death worldwide, but only symptomatic therapies are available for terminal illness. This in part reflects a lack of biomimetic in vitro models that can imitate the complex environment and physiology of the lung. Here, a copolymeric membrane consisting of poly(ε-)caprolactone and gelatin with tunable properties, resembling the main characteristics of the alveolar basement membrane is introduced. The thin bioinspired membrane (0.5 μm) is stretchable (up to 25% linear strain) with appropriate surface wettability and porosity for culturing lung epithelial cells under air–liquid interface conditions. The unique biphasic concept of this membrane provides optimum characteristics for initial cell growth (phase I) and then switch to biomimetic properties for cyclic cell-stretch experiments (phase II). It is showed that physiologic cyclic mechanical stretch improves formation of F-actin cytoskeleton filaments and tight junctions while non-physiologic over-stretch induces cell apoptosis, activates inflammatory response (IL-8), and impairs epithelial barrier integrity. It is also demonstrated that cyclic physiologic stretch can enhance the cellular uptake of nanoparticles. Since this membrane offers considerable advantages over currently used membranes, it may lead the way to more biomimetic in vitro models of the lung for translation of in vitro response studies into clinical outcome.
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| 19. |
- Doryab, Ali, et al.
(författare)
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Evolution of Bioengineered Lung Models : Recent Advances and Challenges in Tissue Mimicry for Studying the Role of Mechanical Forces in Cell Biology
- 2019
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Ingår i: Advanced Functional Materials. - : Wiley. - 1616-301X .- 1616-3028.
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Forskningsöversikt (refereegranskat)abstract
- Mechanical stretch under both physiological (breathing) and pathophysiological (ventilator-induced) conditions is known to significantly impact all cellular compartments in the lung, thereby playing a pivotal role in lung growth, regeneration and disease development. In order to evaluate the impact of mechanical forces on the cellular level, in vitro models using lung cells on stretchable membranes have been developed. Only recently have some of these cell-stretching devices become suitable for air–liquid interface cell cultures, which is required to adequately model physiological conditions for the alveolar epithelium. To reach this goal, a multi-functional membrane for cell growth balancing biophysical and mechanical properties is critical to mimic (patho)physiological conditions. In this review, i) the relevance of cyclic mechanical forces in lung biology is elucidated, ii) the physiological range for the key parameters of tissue stretch in the lung is described, and iii) the currently available in vitro cell-stretching devices are discussed. After assessing various polymers, it is concluded that natural-synthetic copolymers are promising candidates for suitable stretchable membranes used in cell-stretching models. This work provides guidance on future developments in biomimetic in vitro models of the lung with the potential to function as a template for other organ models (e.g., skin, vessels).
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| 20. |
- Gerckens, Michael, et al.
(författare)
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Generation of Human 3D Lung Tissue Cultures (3D-LTCs) for Disease Modeling
- 2019
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Ingår i: Journal of visualized experiments : JoVE. - : MyJove Corporation. - 1940-087X. ; :144
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Tidskriftsartikel (refereegranskat)abstract
- Translation of novel discoveries to human disease is limited by the availability of human tissue-based models of disease. Precision-cut lung slices (PCLS) used as 3D lung tissue cultures (3D-LTCs) represent an elegant and biologically highly relevant 3D cell culture model, which highly resemble in situ tissue due to their complexity, biomechanics and molecular composition. Tissue slicing is widely applied in various animal models. 3D-LTCs derived from human PCLS can be used to analyze responses to novel drugs, which might further help to better understand the mechanisms and functional effects of drugs in human tissue. The preparation of PCLS from surgically resected lung tissue samples of patients, who experienced lung lobectomy, increases the accessibility of diseased and peritumoral tissue. Here, we describe a detailed protocol for the generation of human PCLS from surgically resected soft-elastic patient lung tissue. Agarose was introduced into the bronchoalveolar space of the resectates, thus preserving lung structure and increasing the tissue's stiffness, which is crucial for subsequent slicing. 500 µm thick slices were prepared from the tissue block with a vibratome. Biopsy punches taken from PCLS ensure comparable tissue sample sizes and further increase the amount of tissue samples. The generated lung tissue cultures can be applied in a variety of studies in human lung biology, including the pathophysiology and mechanisms of different diseases, such as fibrotic processes at its best at (sub-)cellular levels. The highest benefit of the 3D-LTC ex vivo model is its close representation of the in situ human lung in respect of 3D tissue architecture, cell type diversity and lung anatomy as well as the potential for assessment of tissue from individual patients, which is relevant to further develop novel strategies for precision medicine.
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| 21. |
- Ghaidan, Haider, et al.
(författare)
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Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.
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| 22. |
- Ikonomou, Laertis, et al.
(författare)
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Translating Basic Research into Safe and Effective Cell-based Treatments for Respiratory Diseases
- 2019
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Ingår i: Annals of the American Thoracic Society. - 2325-6621. ; 16:6, s. 657-668
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Forskningsöversikt (refereegranskat)abstract
- Respiratory diseases, such as chronic obstructive pulmonary disease and pulmonary fibrosis, result in severely impaired quality of life and impose significant burdens on healthcare systems worldwide. Current disease management involves pharmacologic interventions, oxygen administration, reduction of infections, and lung transplantation in advanced disease stages. An increasing understanding of mechanisms of respiratory epithelial and pulmonary vascular endothelial maintenance and repair and the underlying stem/progenitor cell populations, including but not limited to airway basal cells and type II alveolar epithelial cells, has opened the possibility of cell replacement-based regenerative approaches for treatment of lung diseases. Further potential for personalized therapies, including in vitro drug screening, has been underscored by the recent derivation of various lung epithelial, endothelial, and immune cell types from human induced pluripotent stem cells. In parallel, immunomodulatory treatments using allogeneic or autologous mesenchymal stromal cells have shown a good safety profile in clinical investigations for acute inflammatory conditions such as acute respiratory distress syndrome and septic shock. As yet, no cell-based therapy has been shown to be both safe and effective for any lung disease. Despite the investigational status of cell-based interventions for lung diseases, businesses that market unproven, unlicensed and potentially harmful cell-based interventions for respiratory diseases have proliferated in the U.S. and worldwide. The current status of various cell-based regenerative approaches for lung disease as well as the effect of the regulatory environment on clinical translation of such approaches are presented and critically discussed in this review.
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| 23. |
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| 24. |
- Jiang, Dongsheng, et al.
(författare)
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Two succeeding fibroblastic lineages drive dermal development and the transition from regeneration to scarring
- 2018
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 20:4, s. 422-431
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Tidskriftsartikel (refereegranskat)abstract
- During fetal development, mammalian back-skin undergoes a natural transition in response to injury, from scarless regeneration to skin scarring. Here, we characterize dermal morphogenesis and follow two distinct embryonic fibroblast lineages, based on their history of expression of the engrailed 1 gene. We use single-cell fate-mapping, live three dimensional confocal imaging and in silico analysis coupled with immunolabelling to reveal unanticipated structural and regional complexity and dynamics within the dermis. We show that dermal development and regeneration are driven by engrailed 1-history-naive fibroblasts, whose numbers subsequently decline. Conversely, engrailed 1-history-positive fibroblasts possess scarring abilities at this early stage and their expansion later on drives scar emergence. The transition can be reversed, locally, by transplanting engrailed 1-naive cells. Thus, fibroblastic lineage replacement couples the decline of regeneration with the emergence of scarring and creates potential clinical avenues to reduce scarring.
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| 25. |
- Lehmann, Mareike, et al.
(författare)
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Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology 06 Biological Sciences 0601 Biochemistry and Cell Biology
- 2018
-
Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. Methods: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. Results: Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. Conclusions: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.
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| 26. |
- Marazioti, Antonia, et al.
(författare)
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KRAS signaling in malignant pleural mesothelioma
- 2022
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRASG12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRASG12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.
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| 27. |
- Melo-Narváez, M. Camila, et al.
(författare)
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Lung regeneration : implications of the diseased niche and ageing
- 2020
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Ingår i: European Respiratory Review. - : European Respiratory Society (ERS). - 0905-9180 .- 1600-0617. ; 29:157
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Tidskriftsartikel (refereegranskat)abstract
- Most chronic and acute lung diseases have no cure, leaving lung transplantation as the only option. Recent work has improved our understanding of the endogenous regenerative capacity of the lung and has helped identification of different progenitor cell populations, as well as exploration into inducing endogenous regeneration through pharmaceutical or biological therapies. Additionally, alternative approaches that aim at replacing lung progenitor cells and their progeny through cell therapy, or whole lung tissue through bioengineering approaches, have gained increasing attention. Although impressive progress has been made, efforts at regenerating functional lung tissue are still ineffective. Chronic and acute lung diseases are most prevalent in the elderly and alterations in progenitor cells with ageing, along with an increased inflammatory milieu, present major roadblocks for regeneration. Multiple cellular mechanisms, such as cellular senescence and mitochondrial dysfunction, are aberrantly regulated in the aged and diseased lung, which impairs regeneration. Existing as well as new human in vitro models are being developed, improved and adapted in order to study potential mechanisms of lung regeneration in different contexts. This review summarises recent advances in understanding endogenous as well as exogenous regeneration and the development of in vitro models for studying regenerative mechanisms.
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| 28. |
- Petrou, Cassandra L., et al.
(författare)
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Clickable, hybrid hydrogels as tissue culture platforms for modeling chronic pulmonary diseases in vitro
- 2019
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Ingår i: Society for Biomaterials Annual Meeting and Exposition 2019 : The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting - The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. - 9781510883901 ; 40
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Konferensbidrag (refereegranskat)abstract
- Statement of Purpose: Many chronic pulmonary diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD), are complex and poorly understood. While great progress has been made to elucidate the cellular and molecular pathways underlying these diseases, treatment options remain limited. The dynamic alterations in mechanical properties and composition of the ECM that occur during pathologic tissue remodeling have been extensively studied as a major driver of cellular activation and disease progression. However, current in vitro models of pulmonary tissues rely almost exclusively on naturally derived materials, such as Matrigel, collagen or decellularized ECM (dECM), which provide biological activity but cannot be easily tuned to emulate the time-dependent changes in mechanical properties that occur during disease progression. We aim to develop a new class of clickable, dynamically tunable hybrid hydrogels that will allow for the manipulation of microenvironmental mechanical properties through a two-stage polymerization process while also maintaining the complex biological composition of the lung ECM to provide a new tool for studying cell behavior in vitro. Using PH as a model, this hydrogel system will contain dECM from healthy and pathologic lung tissue in order to study the influence of both composition and dynamic mechanical properties on the initiation and progression of PH. Here, we determined the primary amine content in Rat-Tail Collagen Type I (Col I) and three decellularized porcine lung samples. We converted free amines to thiol groups using Traut’s reagent. These thiol groups will ultimately be used to crosslink polyethylene glycol alpha methacrylate (PEGαMA) off-stoichiometry in a Michael addition reaction to form the hybrid hydrogel that can later be stiffened through a secondary, light-initiated homopolymerization of MA moieties to emulate disease progression in vitro (Fig 1A).
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| 29. |
- Ptasinski, Victoria, et al.
(författare)
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Modeling fibrotic alveolar transitional cells with pluripotent stem cell-derived alveolar organoids
- 2023
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Ingår i: Life Science Alliance. - 2575-1077. ; 6:8
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Tidskriftsartikel (refereegranskat)abstract
- Repeated injury of the lung epithelium is proposed to be the main driver of idiopathic pulmonary fibrosis (IPF). However, available therapies do not specifically target the epithelium and human models of fibrotic epithelial damage with suitability for drug discovery are lacking. We developed a model of the aberrant epithelial reprogramming observed in IPF using alveolar organoids derived from human-induced pluripotent stem cells stimulated with a cocktail of pro-fibrotic and inflammatory cytokines. Deconvolution of RNA-seq data of alveolar organoids indicated that the fibrosis cocktail rapidly increased the proportion of transitional cell types including the KRT5-/KRT17+ aberrant basaloid phenotype recently identified in the lungs of IPF patients. We found that epithelial reprogramming and extracellular matrix (ECM) production persisted after removal of the fibrosis cocktail. We evaluated the effect of the two clinically approved compounds for IPF, nintedanib and pirfenidone, and found that they reduced the expression of ECM and pro-fibrotic mediators but did not completely reverse epithelial reprogramming. Thus, our system recapitulates key aspects of IPF and is a promising system for drug discovery.
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| 30. |
- Ptasinski, Victoria, et al.
(författare)
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Targeting Alveolar Repair in Idiopathic Pulmonary Fibrosis
- 2021
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 65:4, s. 347-347
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic pulmonary fibrosis is a fatal interstitial lung disease with limited therapeutic options. Current evidence suggests that IPF may be initiated by repeated epithelial injury in the distal lung followed by abnormal wound healing responses which occur due to intrinsic and extrinsic factors. Mechanisms contributing to chronic damage of the alveolar epithelium in IPF include dysregulated cellular processes such as apoptosis, senescence, abnormal activation of developmental pathways, aging, as well as genetic mutations. Therefore, targeting the regenerative capacity of the lung epithelium is an attractive approach in the development of novel therapies for IPF. Endogenous lung regeneration is a complex process involving coordinated cross-talk between multiple cell types and re-establishment of a normal extracellular matrix environment. This review will describe the current knowledge of reparative epithelial progenitor cells in the alveolar region of the lung and discuss potential novel therapeutic approaches for IPF focusing on endogenous alveolar repair. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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| 31. |
- Stegmayr, John, et al.
(författare)
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Isolation of high yield and quality RNA from human precision-cut lung slices for RNA-sequencing and computational integration with larger patient cohorts
- 2021
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 320:2, s. 232-240
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Tidskriftsartikel (refereegranskat)abstract
- Precision-cut lung slices (PCLS) have gained increasing interest as a model to study lung biology/disease and screening novel therapeutics. In particular, PCLS derived from human tissue can better recapitulate some aspects of lung biology/disease as compared to animal models. Several experimental readouts have been established for use with PCLS, but obtaining high yield and quality RNA for downstream analysis has remained challenging. This is particularly problematic for utilizing the power of next-generation sequencing techniques, such as RNA-sequencing (RNA-seq), for non-biased and high through-put analysis of PCLS human cohorts. In the current study, we present a novel approach for isolating high quality RNA from a small amount of tissue, including diseased human tissue, such as idiopathic pulmonary fibrosis (IPF). We show that the RNA isolated using this method has sufficient quality for RT-qPCR and RNA-seq analysis. Furthermore, the RNA-seq data from human PCLS could be used in several established computational pipelines, including deconvolution of bulk RNA-seq data using publicly available single-cell RNA-seq data. Deconvolution using Bisque revealed a diversity of cell populations in human PCLS, including several immune cell populations, which correlated with cell populations known to be present and aberrant in human disease.
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| 32. |
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| 33. |
- Stenlo, Martin, et al.
(författare)
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Increased particle flow rate from airways precedes clinical signs of ARDS in a porcine model of LPS-induced acute lung injury
- 2020
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 318:3, s. 510-517
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Tidskriftsartikel (refereegranskat)abstract
- Acute respiratory distress syndrome (ARDS) is a common cause of death in the intensive care unit, with mortality rates of ~30-40%. To reduce invasive diagnostics such as bronchoalveolar lavage and time-consuming in-hospital transports for imaging diagnostics, we hypothesized that particle flow rate (PFR) pattern from the airways could be an early detection method and contribute to improving diagnostics and optimizing personalized therapies. Porcine models were ventilated mechanically. Lipopolysaccharide (LPS) was administered endotracheally and in the pulmonary artery to induce ARDS. PFR was measured using a customized particles in exhaled air (PExA 2.0) device. In contrast to control animals undergoing mechanical ventilation and receiving saline administration, animals who received LPS developed ARDS according to clinical guidelines and histologic assessment. Plasma levels of TNF-α and IL-6 increased significantly compared with baseline after 120 and 180 min, respectively. On the other hand, the PFR significantly increased and peaked 60 min after LPS administration, i.e., ~30 min before any ARDS stage was observed with other well-established outcome measurements such as hypoxemia, increased inspiratory pressure, and lower tidal volumes or plasma cytokine levels. The present results imply that PFR could be used to detect early biomarkers or as a clinical indicator for the onset of ARDS.
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| 34. |
- Tas, Sinem, et al.
(författare)
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3D printing of decellularised porcine lung ECM
- 2019
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Ingår i: Society for Biomaterials Annual Meeting and Exposition 2019 : The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting - The Pinnacle of Biomaterials Innovation and Excellence - Transactions of the 42nd Annual Meeting. - 9781510883901 ; 40, s. 962-962
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Konferensbidrag (refereegranskat)abstract
- Statement of Purpose: Chronic lung diseases are one of the major health problems that cause death and disability. Approximately 65 million people suffer from chronic lung diseases, and the number of patients is predicted to increase worldwide 1 . Lung transplantation is the only available treatment option for patients at end-stage disease. However, there is a chronic shortage of donor organs, resulting in a large unmet clinical need. To tackle this issue, the concept of transplantable bioengineered lungs has been proposed as a solution which might help to meet current transplantation needs 2 One of the ways to potentially build complex lung structure is 3D bioprinting, but bioinks which are compatible with 3D printers, support cell growth, and can maintain appropriate mechanical stability are unknown. In this regard, decellularized extracellular matrix (dECM) based materials are considered as a potential novel source of material for bioinks because they have been shown in other contexts to provide a suitable microenvironment for regeneration. However, there has been no investigation of their use in 3D printing of complex shapes. In this study, we evaluated the rheological properties of porcine lungderived dECM solutions and hydrogels to assess their suitability for 3D printing and to determine parameters which can be used to produce stable structures.
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| 35. |
- Tas, Sinem, et al.
(författare)
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Advanced manufacturing: three-dimensional printing and bioprinting of models of lung and airways
- 2022
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Ingår i: 3D Lung Models for Regenerating Lung Tissue. - 9780323908726 - 9780323908719 ; , s. 171-195
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Bokkapitel (refereegranskat)abstract
- Recent advances in materials science coupled with advanced manufacturing techniques have opened up new possibilities for generating sophisticated models of lung and airways containing cells. These models can be used for studying normal tissue homeostasis as well as for modeling lung development, disease, and regeneration. Three-dimensional (3D) printing has emerged as a leading advanced manufacturing technique for generating models as well as producing clinically relevant constructs. In fact, 3D-printed, cell-free support structures have already been used clinically in a few case reports for airways. While 3D bioprinting is poised to play a major role in both preclinical and clinical science, only a few constructs containing cells have been made to date. Preclinical models of 3D-bioprinted tracheas containing cells show promise, but there is a paucity of reports for distal lung, owing to a lack of bioinks. This chapter discusses the use of advanced manufacturing to bioengineer 3D constructs for lung and airways.
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| 36. |
- Ulke, Henrik M, et al.
(författare)
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The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis
- 2019
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 61:6, s. 713-726
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Tidskriftsartikel (refereegranskat)abstract
- Idiopathic pulmonary fibrosis (IPF) and lung cancer represent progressive lung diseases with a poor prognosis. IPF represents a risk factor for the development of lung cancer, and the incidence of lung cancer is increased in patients with IPF. Disease pathogenesis of IPF and lung cancer involves common genetic alterations, dysregulated pathways, and the emergence of hyperplastic and metaplastic epithelial cells. Here, we aimed to identify novel, common mediators that might contribute to epithelial cell reprogramming in IPF. Gene set enrichment analysis (GSEA) of publicly available non-small cell lung cancer (NSCLC) and IPF datasets revealed a common pattern of misregulated genes, linked to cell proliferation and transformation. The oncogene epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor (GEF) for Rho GTPases, was highly enriched in both, IPF and NSCLC, compared to non-diseased controls. Increased expression of ECT2 was verified by qPCR and Western blotting in bleomycin-induced lung fibrosis and human IPF tissue. Immunohistochemistry demonstrated strong expression of ECT2 staining in hyperplastic type II alveolar epithelial (ATII) cells in IPF, as well as its colocalization with PCNA, a well-known proliferation marker. Increased ECT2 expression coincided with enhanced proliferation of primary mouse ATII cells as analyzed by flow cytometric analysis. ECT2 knockdown in ATII cells resulted in decreased proliferation and collagen I expression in vitro. These data suggest that the oncogene ECT2 contributes to epithelial cell reprogramming in IPF and further underline the hyperplastic, proliferative ATII cell as a potential target in patients with IPF and lung cancer.
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| 37. |
- van der Velden, Jos L., et al.
(författare)
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TGF-β1-induced deposition of provisional extracellular matrix by tracheal basal cells promotes epithelial-to-mesenchymal transition in a c-Jun NH2-terminal kinase-1-dependent manner
- 2018
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 314:6, s. 984-997
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Tidskriftsartikel (refereegranskat)abstract
- Epithelial cells have been suggested as potential drivers of lung fibrosis, although the epithelial-dependent pathways that promote fibrogenesis remain unknown. Extracellular matrix is increasingly recognized as an environment that can drive cellular responses in various pulmonary diseases. In this study, we demonstrate that transforming growth factor-β1 (TGF-β1)-stimulated mouse tracheal basal (MTB) cells produce provisional matrix proteins in vitro, which initiate mesenchymal changes in subsequently freshly plated MTB cells via Rho kinase-and c-Jun NH2-terminal kinase (JNK1)-dependent processes. Repopulation of decellularized lung scaffolds, derived from mice with bleomycin-induced fibrosis or from patients with idiopathic pulmonary fibrosis, with wild-type MTB cells resulted in a loss of epithelial gene expression and augmentation of mesenchymal gene expression compared with cells seeded into decellularized normal lungs. In contrast, Jnk1-/- basal cells seeded into fibrotic lung scaffolds retained a robust epithelial expression profile, failed to induce mesenchymal genes, and differentiated into club cell secretory protein-expressing cells. This new paradigm wherein TGF-β1-induced extracellular matrix derived from MTB cells activates a JNK1-dependent mesenchymal program, which impedes subsequent normal epithelial cell homeostasis, provides a plausible scenario of chronic aberrant epithelial repair, thought to be critical in lung fibrogenesis. This study identifies JNK1 as a possible target for inhibition in settings wherein reepithelialization is desired.
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| 38. |
- Wagner, Darcy E.
(författare)
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Bioengineering Approaches for the Distal Lung
- 2021
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Ingår i: Encyclopedia of Respiratory Medicine, Second Edition. - 9780081027240 - 9780081027233 ; 1, s. 788-795
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Bokkapitel (refereegranskat)abstract
- Chronic and acute lung diseases are the third and fourth leading causes of global mortality. Distal lung tissue is severely damaged in many lung diseases, causing respiratory insufficiency from loss of surface area available for gas exchange. Current therapies aim at relieving symptoms and are unable to reverse disease. Lung transplantation remains the only potential curative option at end-stage disease but is severely limited by a lack of suitable donor lungs and low long-term survival. Bioengineering lung tissue or bioengineering cells with biomaterials for transplantation is an exciting new approach to (re)generate tissue to close this large unmet clinical need.
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| 39. |
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| 40. |
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