| 1. |
- Wasserstrom, Sebastian, et al.
(författare)
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Model visualization : from micro to macro
- 2022
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Ingår i: 3D lung models for regenerating lung tissue. - 9780323908719 ; , s. 207-221
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Bokkapitel (refereegranskat)abstract
- Because of increasing demand, rapid development of in vitro and in vivo models to be used to study lung regeneration and lung repair has occurred during the last years. Even if imaging has always been an important tool in diagnosing disease and validating models, the current disease models, including three-dimensional (3D) lung models, put a higher demand on advanced imaging techniques. Moreover, choosing the most relevant technique for a specific question is not a trivial task, and the rapid development of new techniques has not made this task easier. Therefore the aim of this chapter is to provide an overview of different advanced imaging techniques that can be used to evaluate and validate 3D lung models, to provide a discussion on the current state of the art, and to list the pros and cons of the available techniques.
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| 2. |
- 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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| 3. |
- Zimmerman, Malin, et al.
(författare)
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Temporal trend of autonomic nerve function and HSP27, MIF and PAI-1 in type 1 diabetes
- 2017
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Ingår i: Journal of Clinical and Translational Endocrinology. - : Elsevier BV. - 2214-6237. ; 8, s. 15-21
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Tidskriftsartikel (refereegranskat)abstract
- Aim Diabetes mellitus type 1 (T1D) has numerous complications including autonomic neuropathy, i.e. dysfunction of the autonomous nervous system. This study focuses on Heat Shock Protein 27 (HSP27), Macrophage Migration Inhibitory Factor (MIF), Plasminogen Activator Inhibitor-1 (PAI-1) and HbA1c and their possible roles in effects of diabetes on the autonomic nervous system. Methods Patients with T1D (n = 32, 41% women) were recruited in 1985 and followed up on four occasions (1989, 1993, 1998, and 2005). Autonomic function was tested using expiration/inspiration (E/I-ratio). Blood samples, i.e. HSP27 (last three occasions), MIF, PAI-1 (last two occasions) and HbA1c (five occasions), were analyzed. Results Autonomic nerve function deteriorated over time during the 20-year-period, but levels of HSP27, MIF, and PAI-1 were not associated with cardiovascular autonomic neuropathy. MIF and PAI-1 were lower in T1D than in healthy controls in 2005. Increased HbA1c correlated with a decrease in E/I-ratio. Conclusions Neither the neuroprotective substance HSP27 nor the inflammatory substances, MIF and PAI-1 were associated with measures of cardiovascular autonomic nerve function, but a deterioration of such function was observed in relation to increasing HbA1c in T1D during a 20-year follow-up period. Improved glucose control might be associated with protection against autonomic neuropathy in T1D.
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| 4. |
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3D Lung Models for Regenerating Lung Tissue
- 2022
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Samlingsverk (redaktörskap) (refereegranskat)abstract
- 3D Lung Models for Regenerating Lung Tissue is a comprehensive summary on the current state of art 3D lung models and novel techniques that can be used to regenerate lung tissue. Written by experts in the field, readers can expect to learn more about 3D lung models, novel techniques including bioprinting and advanced imaging techniques, as well as important knowledge about the complexity of the lung and its extracellular matrix composition.Structured into 15 different chapters, the book spans from the original 2D cell culture model on plastic, to advanced 3D lung models such as using human extracellular matrix protein. In addition, the last chapters cover new techniques including 3D printing, bioprinting, and artificial intelligence that can be used to drive the field forward and some future perspectives. This highly topical book with chapters on everything from the complexity of the lung and its microenvironment to cutting-edge 3D lung models, represents an exciting body of work that can be used by researchers during study design, grant writing, as teaching material, or to stay updated with the progression of the field.Key Features A comprehensive summary of advanced 3D lung models written by the experts in the respiratory field Explore novel techniques that can be used to evaluate and improve 3D lung models, including techniques such as 3D printing, bioprinting, and artificial intelligence Explains what extracellular matrix is, the complexity of the lung microenvironment, and why this knowledge is important for creating a functional bioartificial lung
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| 5. |
- Abreu, Soraia Carvalho, et al.
(författare)
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Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells
- 2020
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1040-0605 .- 1522-1504.
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Tidskriftsartikel (refereegranskat)abstract
- Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.
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| 6. |
- Abreu, Soraia Carvalho, et al.
(författare)
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Lung Inflammatory Environments Differentially Alter Mesenchymal Stromal Cell Behavior
- 2019
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 317:6, s. 823-831
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal (stem) cells (MSCs) are increasingly demonstrated to ameliorate experimentally-induced lung injuries through disease-specific anti-inflammatory actions, thus suggesting that different in vivo inflammatory environments can influence MSC actions. To determine the effects of different representative inflammatory lung conditions, human bone marrow-derived MSCs (hMSCs) were exposed to in vitro culture conditions from bronchoalveolar lavage fluid (BALF) samples obtained from patients with either the acute respiratory distress syndrome (ARDS) or with other lung diseases including acute respiratory exacerbations of cystic fibrosis (CF) (non-ARDS). hMSCs were subsequently assessed for time- and BALF concentration-dependent effects on mRNA expression of selected pro- and anti-inflammatory mediators, and for overall patterns of gene and mRNA expression. Both common and disease specific-patterns were observed in gene expression of different hMSC mediators, notably interleukin (IL)-6. Conditioned media obtained from non-ARDS BALF-exposed hMSCs was more effective in promoting an anti-inflammatory phenotype in monocytes than was conditioned media from ARDS BALF-exposed hMSCs. Neutralizing IL-6 in the conditioned media promoted generation of anti-inflammatory monocyte phenotype. These results demonstrated that different lung inflammatory environments differentially alter hMSC behavior. Further identification of these interactions and the driving mechanisms may influence clinical use of MSCs for treating lung diseases.
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| 7. |
- Andersson Sjöland, Annika, et al.
(författare)
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Fibroblast phenotypes and their activity are changed in the wound healing process after lung transplantation.
- 2011
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Ingår i: The Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1557-3117 .- 1053-2498. ; 30, s. 945-954
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lung transplantation (LTx) is established as a life-saving treatment in end-stage lung disease. However, long-term survival is hampered by the development of chronic rejection, almost synonymous with bronchiolitis obliterans syndrome (BOS). The rejection is characterized by deposition of extracellular matrix in small airways. Fibroblasts/myofibroblasts are the main producers of extracellular matrix molecules such as proteoglycans. This study compared fibroblast phenotype and activity in the wound healing process at different points after LTx in patients who later did, or did not, develop BOS. METHODS: Distally derived fibroblasts from patients 6 and 12 months after LTx and from healthy controls were analyzed for production of the proteoglycans versican, perlecan, biglycan, and decorin, with and without transforming growth factor (TGF)-β(1). Fibroblast migration and proliferation were also studied. RESULTS: At 6 and 12 months after LTx, versican production was higher in fibroblasts from LTx patients (p < 0.01 p < 0.01) than from controls. Fibroblasts from patients who later developed BOS were more responsive to TGF-β(1)-induced synthesis of versican and biglycan than patients without signs of rejection (p < 0.05). Production of perlecan and decorin was negatively correlated with fibroblast proliferation in fibroblasts at 6 months after LTx. In a more detailed case study of 2 patients, one with and one without BOS, the altered proteoglycan profile was associated with impaired lung function. CONCLUSIONS: LTx changes the phenotype of fibroblasts to a non-proliferative but extracellular matrix-producing cell due to wound healing involving TGF-β(1). If not controlled, this may lead to development of BOS.
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| 8. |
- Andersson Sjöland, Annika, et al.
(författare)
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Versican in inflammation and tissue remodelling: the impact on lung disorders.
- 2015
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Ingår i: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 25:3, s. 243-251
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Forskningsöversikt (refereegranskat)abstract
- Versican is a proteoglycan that has many different roles in tissue homeostasis and inflammation. The biochemical structure is comprised of four different types of the core protein with attached glycosaminoglycans that can be sulphated to various extents and has the capacity to regulate differentiation of different cell types, migration, cell adhesion, proliferation, tissue stabilization and inflammation. Versican's regulatory properties are of importance during both homeostasis and changes that lead to disease progression. The glycosaminoglycans that are attached to the core protein are of the chondroitin sulfate/dermatan sulfate type and are known to be important in inflammation through interactions with cytokines and growth factors. For a more complex understanding of versican it is of importance to study the tissue niche, where the wound healing process in both healthy and diseased conditions take place. In previous studies our group has identified changes in the amount of the multifaceted versican in chronic lung disorders such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome, which could be a result of pathologic, transforming growth factor β driven, on-going remodelling processes. Reversely, the context of versican in its niche is of great importance since versican has been reported to have a beneficial role in other contexts e.g. emphysema. Here we explore the vast mechanisms of versican in healthy lung and in lung disorders.
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| 9. |
- Blank Savukinas, Ulrika, et al.
(författare)
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The Bystander Effect : Mesenchymal Stem Cell-Mediated Lung Repair
- 2016
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 34:6, s. 1437-1444
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Forskningsöversikt (refereegranskat)abstract
- Mesenchymal stem or stromal cells (MSCs), a heterogeneous subset of adult stem/progenitor cells, have surfaced as potential therapeutic units with significant clinical benefit for a wide spectrum of disease conditions, including those affecting the lung. Although MSCs carry both self-renewal and multilineage differentiation abilities, current dogma holds that MSCs mainly contribute to tissue regeneration and repair by modulating the host tissue via secreted cues. Thus, the therapeutic benefit of MSCs is thought to derive from so called bystander effects. The regenerative mechanisms employed by MSCs in the lung include modulation of the immune system as well as promotion of epithelial and endothelial repair. Apart from secreted factors, a number of recent findings suggest that MSCs engage in mitochondrial transfer and shedding of membrane vesicles as a means to enhance tissue repair following injury. Furthermore, it is becoming increasingly clear that MSCs are an integral component of epithelial lung stem cell niches. As such, MSCs play an important role in coupling information from the environment to stem and progenitor populations, such that homeostasis can be ensured even in the face of injury. It is the aim of this review to outline the major mechanisms by which MSCs contribute to lung regeneration, synthesizing recent preclinical findings with data from clinical trials and potential for future therapy
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| 10. |
- Burgy, Olivier, et al.
(författare)
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New players in chronic lung disease identified at the European Respiratory Society International Congress in Paris 2018 : From microRNAs to extracellular vesicles
- 2018
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Ingår i: Journal of Thoracic Disease. - : AME Publishing Company. - 2072-1439 .- 2077-6624. ; 10, s. 2983-2987
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Tidskriftsartikel (refereegranskat)abstract
- Since the first description of microRNAs (miRNAs) in 1993 (1) a large and growing number of studies has explored their roles across a variety of biomedical research disciplines, including lung biology. According to GENCODE (version 27) (2), 1881 of the >7,500 human small non-coding RNAs are miRNAs. These 20–25 nucleotide-long, regulatory RNAs are involved in the translational regulation of gene expression principally via binding to miRNA recognition elements largely in the 3' untranslated regions of target mRNAs. Upon binding they can induce mRNA degradation, deadenylation or inhibition of their translation, leading to decreased target gene expression (3). Originally described to play important roles in developmental biology, miRNAs have since been found to have significant roles in a multitude of biological processes. Expression levels of miRNAs vary greatly between cells and tissues, and aberrant levels of miRNA are associated with many diseases in humans. In fact, these non-coding RNA molecules are now recognized as major regulators in the development and progression of various chronic lung diseases, including cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma (4-9).
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| 11. |
- D. Ubags, Niki, et al.
(författare)
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ERS International Congress, Madrid, 2019: highlights from the Basic and translational Science Assembly
- 2020
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Ingår i: ERJ Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- In this review, the Basic and Translational Sciences Assembly of the European Respiratory Society (ERS) provides an overview of the 2019 ERS International Congress highlights. In particular, we discuss how the novel and very promising technology of single cell sequencing has led to the development of a comprehensive map of the human lung, the lung cell atlas, including the discovery of novel cell types and new insights into cellular trajectories in lung health and disease. Further, we summarise recent insights in the field of respiratory infections, which can aid in a better understanding of the molecular mechanisms underlying these infections in order to develop novel vaccines and improved treatment options. Novel concepts delineating the early origins of lung disease are focused on the effects of pre- and post-natal exposures on neonatal lung development and long-term lung health. Moreover, we discuss how these early life exposures can affect the lung microbiome and respiratory infections. In addition, the importance of metabolomics and mitochondrial function analysis to subphenotype chronic lung disease patients according to their metabolic program is described. Finally, basic and translational respiratory science is rapidly moving forward and this will be beneficial for an advanced molecular understanding of the mechanisms underlying a variety of lung diseases. In the long-term this will aid in the development of novel therapeutic targeting strategies in the field of respiratory medicine.
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| 12. |
- dos Santos, Claudia C., et al.
(författare)
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The MSC-EV-microRNAome : A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS
- 2024
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Ingår i: Cells. - 2073-4409. ; 13:2
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Forskningsöversikt (refereegranskat)abstract
- Mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) have emerged as innovative therapeutic agents for the treatment of sepsis and acute respiratory distress syndrome (ARDS). Although their potential remains undisputed in pre-clinical models, this has yet to be translated to the clinic. In this review, we focused on the role of microRNAs contained in MSC-derived EVs, the EV microRNAome, and their potential contribution to therapeutic mechanisms of action. The evidence that miRNA transfer in MSC-derived EVs has a role in the overall therapeutic effects is compelling. However, several questions remain regarding how to reconcile the stochiometric issue of the low copy numbers of the miRNAs present in the EV particles, how different miRNAs delivered simultaneously interact with their targets within recipient cells, and the best miRNA or combination of miRNAs to use as therapy, potency markers, and biomarkers of efficacy in the clinic. Here, we offer a molecular genetics and systems biology perspective on the function of EV microRNAs, their contribution to mechanisms of action, and their therapeutic potential.
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| 13. |
- Dunbar, Hazel, et al.
(författare)
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The inflammatory lung microenvironment; a key mediator in msc licensing
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:11
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Forskningsöversikt (refereegranskat)abstract
- Recent clinical trials of mesenchymal stromal cell (MSC) therapy for various inflammatory conditions have highlighted the significant benefit to patients who respond to MSC administration. Thus, there is strong interest in investigating MSC therapy in acute inflammatory lung conditions, such as acute respiratory distress syndrome (ARDS). Unfortunately, not all patients respond, and evidence now suggests that the differential disease microenvironment present across patients and sub-phenotypes of disease or across disease severities influences MSC licensing, function and therapeutic efficacy. Here, we discuss the importance of licensing MSCs and the need to better under-stand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach.
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| 14. |
- Elowsson Rendin, Linda, et al.
(författare)
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Harnessing the ECM Microenvironment to Ameliorate Mesenchymal Stromal Cell-Based Therapy in Chronic Lung Diseases
- 2021
-
Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 12
-
Forskningsöversikt (refereegranskat)abstract
- It is known that the cell environment such as biomechanical properties and extracellular matrix (ECM) composition dictate cell behaviour including migration, proliferation, and differentiation. Important constituents of the microenvironment, including ECM molecules such as proteoglycans and glycosaminoglycans (GAGs), determine events in both embryogenesis and repair of the adult lung. Mesenchymal stromal/stem cells (MSC) have been shown to have immunomodulatory properties and may be potent actors regulating tissue remodelling and regenerative cell responses upon lung injury. Using MSC in cell-based therapy holds promise for treatment of chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, so far clinical trials with MSCs in COPD have not had a significant impact on disease amelioration nor on IPF, where low cell survival rate and pulmonary retention time are major hurdles to overcome. Research shows that the microenvironment has a profound impact on transplanted MSCs. In our studies on acellular lung tissue slices (lung scaffolds) from IPF patients versus healthy individuals, we see a profound effect on cellular activity, where healthy cells cultured in diseased lung scaffolds adapt and produce proteins further promoting a diseased environment, whereas cells on healthy scaffolds sustain a healthy proteomic profile. Therefore, modulating the environmental context for cell-based therapy may be a potent way to improve treatment using MSCs. In this review, we will describe the importance of the microenvironment for cell-based therapy in chronic lung diseases, how MSC-ECM interactions can affect therapeutic output and describe current progress in the field of cell-based therapy.
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| 15. |
- Enes, Sara Rolandsson, et al.
(författare)
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Healthy versus Inflamed Lung Environments Differentially Effect MSCs
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 58:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite increased interest in MSC-based cell therapies for the acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and understanding of the potential in vivo mechanisms of MSC actions in ARDS remain limited. ARDS is driven by an acute severe innate immune dysregulation, often characterized by inflammation, coagulation, and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined. Aim: To comparatively assess how the inflammatory environment present in ARDS lungs vs. the lung environment present in healthy volunteers alters MSC behaviors. Methods: Clinical grade human bone marrow-derived MSCs (hMSCs) were exposed to bronchoalveolar lavage fluid (BALF) samples obtained from ARDS patients or from healthy volunteers. Following exposure, hMSCs and their conditioned media were evaluated for a broad panel of relevant properties including viability, levels of expression of inflammatory cytokines, gene expression, cell surface HLA expression, and activation of coagulation and complement pathways. Results: Pro-inflammatory, pro-coagulant, and major histocompatibility complex (self recognition) related gene and protein expression was markedly up-regulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. In contrast, these changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples. Conclusion: These data provide new insights into how hMSCs behave in healthy vs. inflamed lung environments strongly suggesting that the inflamed environment in ARDS induces hMSC responses potentially benefical for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.
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| 16. |
- Enes, Sara Rolandsson, et al.
(författare)
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MSC from fetal and adult lungs possess lung-specific properties compared to bone marrow-derived MSC
- 2016
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6, s. 29160-
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cells (MSC) are multipotent cells with regenerative and immune-modulatory properties. Therefore, MSC have been proposed as a potential cell-therapy for bronchiolitis obliterans syndrome (BOS). On the other hand, there are publications demonstrating that MSC might be involved in the development of BOS. Despite limited knowledge regarding the functional role of tissue-resident lung-MSC, several clinical trials have been performed using MSC, particularly bone marrow (BM)-derived MSC, for various lung diseases. We aimed to compare lung-MSC with the well-characterized BM-MSC. Furthermore, MSC isolated from lung-transplanted patients with BOS were compared to patients without BOS. Our study show that lung-MSCs are smaller, possess a higher colony-forming capacity and have a different cytokine profile compared to BM-MSC. Utilizing gene expression profiling, 89 genes including lung-specific FOXF1 and HOXB5 were found to be significantly different between BM-MSC and lung-MSC. No significant differences in cytokine secretion or gene expression were found between MSC isolated from BOS patients compared recipients without BOS. These data demonstrate that lung-resident MSC possess lung-specific properties. Furthermore, these results show that MSC isolated from lung-transplanted patients with BOS do not have an altered phenotype compared to MSC isolated from good outcome recipients.
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| 17. |
- Falcones, Bryan, et al.
(författare)
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hLMSC Secretome Affects Macrophage Activity Differentially Depending on Lung-Mimetic Environments
- 2022
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:12
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cell (MSC)-based therapies for inflammatory diseases rely mainly on the paracrine ability to modulate the activity of macrophages. Despite recent advances, there is scarce information regarding changes of the secretome content attributed to physiomimetic cultures and, especially, how secretome content influence on macrophage activity for therapy. hLMSCs from human donors were cultured on devices developed in house that enabled lung-mimetic strain. hLMSC secretome was analyzed for typical cytokines, chemokines and growth factors. RNA was analyzed for the gene expression of CTGF and CYR61. Human monocytes were differentiated to macrophages and assessed for their phagocytic capacity and for M1/M2 subtypes by the analysis of typical cell surface markers in the presence of hLMSC secretome. CTGF and CYR61 displayed a marked reduction when cultured in lung-derived hydrogels (L-Hydrogels). The secretome showed that lung-derived scaffolds had a distinct secretion while there was a large overlap between L-Hydrogel and the conventionally (2D) cultured samples. Additionally, secretome from L-Scaffold showed an HGF increase, while IL-6 and TNF-α decreased in lung-mimetic environments. Similarly, phagocytosis decreased in a lung-mimetic environment. L-Scaffold showed a decrease of M1 population while stretch upregulated M2b subpopulations. In summary, mechanical features of the lung ECM and stretch orchestrate anti-inflammatory and immunosuppressive outcomes of hLMSCs.
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| 18. |
- Hallgren, Oskar, et al.
(författare)
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Enhanced ROCK1 dependent contractility in fibroblast from chronic obstructive pulmonary disease patients
- 2012
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: During wound healing processes fibroblasts account for wound closure by adopting a contractile phenotype. One disease manifestation of COPD is emphysema which is characterized by destruction of alveolar walls and our hypothesis is that fibroblasts in the COPD lungs differentiate into a more contractile phenotype as a response to the deteriorating environment. Methods: Bronchial (central) and parenchymal (distal) fibroblasts were isolated from lung explants from COPD patients (n = 9) (GOLD stage IV) and from biopsies from control subjects and from donor lungs (n = 12). Tissue-derived fibroblasts were assessed for expression of proteins involved in fibroblast contraction by western blotting whereas contraction capacity was measured in three-dimensional collagen gels. Results: The basal expression of rho-associated coiled-coil protein kinase 1 (ROCK1) was increased in both centrally and distally derived fibroblasts from COPD patients compared to fibroblasts from control subjects (p < 0.001) and (p < 0.01), respectively. Distally derived fibroblasts from COPD patients had increased contractile capacity compared to control fibroblasts (p < 0.01). The contraction was dependent on ROCK1 activity as the ROCK inhibitor Y27632 dose-dependently blocked contraction in fibroblasts from COPD patients. ROCK1-positive fibroblasts were also identified by immunohistochemistry in the alveolar parenchyma in lung tissue sections from COPD patients. Conclusions: Distally derived fibroblasts from COPD patients have an enhanced contractile phenotype that is dependent on ROCK1 activity. This feature may be of importance for the elastic dynamics of small airways and the parenchyma in late stages of COPD.
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| 19. |
- Hawthorne, Ian J., et al.
(författare)
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Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma
- 2023
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Ingår i: Molecular Therapy. - 1525-0016. ; 31:11, s. 3243-3258
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Tidskriftsartikel (refereegranskat)abstract
- Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT7 mice but not in CATT5 or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT7 mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
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| 20. |
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| 21. |
- Kadefors, Måns, et al.
(författare)
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CD105+CD90+CD13+ identifies a clonogenic subset of adventitial lung fibroblasts
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal cells are important components of specified niches in the lung, and can mediate a wide range of processes including tissue regeneration and repair. Dysregulation of these processes can lead to improper remodeling of tissue as observed in several lung diseases. The mesenchymal cells responsible remain poorly described, partially due to the heterogenic nature of the mesenchymal compartment and the absence of appropriate markers. Here, we describe that CD105+CD90+ mesenchymal cells can be divided into two populations based on their expression of CD13/aminopeptidase N (CD105+CD90+CD13− and CD105+CD90+CD13+). By prospective isolation using FACS, we show that both these populations give rise to clonogenic fibroblast-like cells, but with an increased clonogenic and proliferative capacity of CD105+CD90+CD13+ cells. Transcriptomic and spatial analysis pinpoints an adventitial fibroblast subset as the origin of CD105+CD90+CD13+ clonogenic mesenchymal cells in human lung.
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| 22. |
- Kadefors, Måns, et al.
(författare)
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Dipeptidyl peptidase 4 expression is not associated with an activated fibroblast phenotype in idiopathic pulmonary fibrosis
- 2022
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- Dipeptidyl peptidase 4 (DPP4) has been proposed as a marker for activated fibroblasts in fibrotic disease. We aimed to investigate whether a profibrotic DPP4 phenotype is present in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). The presence of DPP4 + fibroblasts in normal and IPF lung tissue was investigated using flow cytometry and immunohistology. In addition, the involvement of DPP4 in fibroblast activation was examined in vitro, using CRISPR/Cas9 mediated genetic inactivation to generate primary DPP4 knockout lung fibroblasts. We observed a reduced frequency of primary DPP4 + fibroblasts in IPF tissue using flow cytometry, and an absence of DPP4 + fibroblasts in pathohistological features of IPF. The in vivo observations were supported by results in vitro showing a decreased expression of DPP4 on normal and IPF fibroblasts after profibrotic stimuli (transforming growth factor β) and no effect on the expression of activation markers (α-smooth muscle actin, collagen I and connective tissue growth factor) upon knockout of DPP4 in lung fibroblasts with or without activation with profibrotic stimuli.
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| 23. |
- Masterson, C. H., et al.
(författare)
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Mesenchymal stem/stromal cell-based therapies for severe viral pneumonia: therapeutic potential and challenges
- 2021
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 9:61, s. 1-21
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Forskningsöversikt (refereegranskat)abstract
- Severe viral pneumonia is a significant cause of morbidity and mortality globally, whether due to outbreaks of endemic viruses, periodic viral epidemics, or the rarer but devastating global viral pandemics. While limited anti-viral therapies exist, there is a paucity of direct therapies to directly attenuate viral pneumonia-induced lung injury, and management therefore remains largely supportive. Mesenchymal stromal/stem cells (MSCs) are receiving considerable attention as a cytotherapeutic for viral pneumonia. Several properties of MSCs position them as a promising therapeutic strategy for viral pneumonia-induced lung injury as demonstrated in pre-clinical studies in relevant models. More recently, early phase clinical studies have demonstrated a reassuring safety profile of these cells. These investigations have taken on an added importance and urgency during the COVID-19 pandemic, with multiple trials in progress across the globe. In parallel with clinical translation, strategies are being investigated to enhance the therapeutic potential of these cells in vivo, with different MSC tissue sources, specific cellular products including cell-free options, and strategies to ‘licence’ or ‘pre-activate’ these cells, all being explored. This review will assess the therapeutic potential of MSC-based therapies for severe viral pneumonia. It will describe the aetiology and epidemiology of severe viral pneumonia, describe current therapeutic approaches, and examine the data suggesting therapeutic potential of MSCs for severe viral pneumonia in pre-clinical and clinical studies. The challenges and opportunities for MSC-based therapies will then be considered.
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| 24. |
- Rolandsson Enes, Sara, et al.
(författare)
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Bioartificial lungs based on de- and recelluarisation approaches: a historical perspective.
- 2020
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Ingår i: Breathe. - : European Respiratory Society (ERS). - 1810-6838 .- 2073-4735. ; 16:4, s. 1-4
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Forskningsöversikt (refereegranskat)abstract
- For patients with end-stage respiratory diseases, such as COPD, interstitial lung diseases and cystic fibrosis, lung transplantation remains the only treatable option. However, due to increasing demand and limited availability of donor lungs, risk of complications such as acute and chronic rejection, and adverse effects of immunosuppressive treatments, this is not an alternative for the majority of this patient group [1, 2]. To meet the rising clinical demand new strategies to increase the number of available lungs for transplantation are needed [2]. One such strategy involves creating a functional lung ex vivo using different de- and recellularisation approaches. In this article, we will provide an overview of three landmark studies on bioartificial lungs published during 2010 that set the base for the direction of this relatively young field.
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| 25. |
- Rolandsson Enes, Sara, et al.
(författare)
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Clinical Application of Stem/Stromal Cells in COPD
- 2019
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Ingår i: Stem Cell-Based Therapy for Lung Disease. - Cham : Springer International Publishing. - 9783030294021 - 9783030294038 ; , s. 97-118
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Bokkapitel (refereegranskat)abstract
- Chronic obstructive pulmonary disease (COPD) is a progressive life-threatening disease that is significantly increasing in prevalence and is predicted to become the third leading cause of death worldwide by 2030. At present, there are no true curative treatments that can stop the progression of the disease, and new therapeutic strategies are desperately needed. Advances in cell-based therapies provide a platform for the development of new therapeutic approaches in severe lung diseases such as COPD. At present, a lot of focus is on mesenchymal stem (stromal) cell (MSC)-based therapies, mainly due to their immunomodulatory properties. Despite increasing number of preclinical studies demonstrating that systemic MSC administration can prevent or treat experimental COPD and emphysema, clinical studies have not been able to reproduce the preclinical results and to date no efficacy or significantly improved lung function or quality of life has been observed in COPD patients. Importantly, the completed appropriately conducted clinical trials uniformly demonstrate that MSC treatment in COPD patients is well tolerated and no toxicities have been observed. All clinical trials performed so far, have been phase I/II studies, underpowered for the detection of potential efficacy. There are several challenges ahead for this field such as standardized isolation and culture procedures to obtain a cell product with high quality and reproducibility, administration strategies, improvement of methods to measure outcomes, and development of potency assays. Moreover, COPD is a complex pathology with a diverse spectrum of clinical phenotypes, and therefore it is essential to develop methods to select the subpopulation of patients that is most likely to potentially respond to MSC administration. In this chapter, we will discuss the current state of the art of MSC-based cell therapy for COPD and the hurdles that need to be overcome.
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| 26. |
- Rolandsson Enes, Sara, et al.
(författare)
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Comparison of the Regenerative Potential for Lung Tissue of Mesenchymal Stromal Cells from Different Sources/Locations Within the Body
- 2019
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Ingår i: Stem Cell-Based Therapy for Lung Disease. - Cham : Springer International Publishing. - 9783030294021 - 9783030294038 ; , s. 35-55
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Bokkapitel (refereegranskat)abstract
- To date, bone marrow-derived mesenchymal stromal cells (MSCs) have been considered the golden standard among MSC cell-based therapies. However, the harvesting of bone marrow is a highly invasive procedure and the number of MSCs isolated is low, and it declines with increasing age. MSCs with immune-regulatory and regenerative properties can be isolated from many different tissues; however, bone marrow-derived MSCs are so far the most thoroughly characterized MSC population. Despite an increased interest in using MSCs for clinical approaches in severe lung disorders, the biological function of MSCs after administration is not completely known, in particular, of MSCs extracted from other tissues than bone marrow aspirates. MSCs do not engraft after infusion, and data demonstrate that the majority of MSCs tend to be cleared from the lungs within a few days, suggesting a fast, short acting, and paracrine effect. Following activation, MSCs produce and secrete mediators, the secretome, that influence the microenvironment and the surrounding resident cells in order to modulate and repair damaged tissue. Exploring the MSC secretome has attracted much attention, and today it is known to consist of an array of molecules that is important for their regenerative and protective abilities. However, recent data suggest that the secretome profiles differ significantly depending on the MSC source, donor site, and external stimulation. In addition, the microenvironment that the infused MSCs encounter most likely plays an important role in influencing the therapeutic effect of MSCs. The composition of the microenvironment is unique in every tissue type and varies by developmental age. Changes in both stiffness and composition drastically affect MSC fate and function. The aim of this chapter is to provide a comparison of the potential of MSCs obtained from different cellular sources, and how they can be used as therapeutic agents to treat lung disorders.
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| 27. |
- Rolandsson Enes, Sara
(författare)
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Mesenchymal stromal cells in lung tissue
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mesenchymal stromal cells (MSC) are multipotent cells with immunomodulatory and regenerative properties. During recent years, the interest in using MSC for clinical approaches for various diseases have increased. The lung field is no exception, and several clinical trials using MSC as a cell-based therapy for severe lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and severe emphysema have been performed. Another severe lung disease where MSC therapy might be an alternative is bronchiolitis obliterans syndrome (BOS), a chronic type of rejection affecting approxamately 50% of lung transplanted patients within five years after transplantation. The exact pathology of BOS is at present not known, but inflammation is thought to be an important driving factor. Despite an increased interest in using MSC as a therapy, the in vivo biological function of endogenous MSC is not completely known. Furthermore, the cellular identity of primary MSC in human lungs has not been reported. The aim of this thesis work has been to provide new insights of MSC in lung tissue, especially after lung transplantation, with respect to origin, tissue-specificity, and extracellular matrix production. Primary and culture-derived MSC were isolated from lung biopsies obtained from lung transplanted patients, fetal lung tissue, and bone marrow aspirates and evaluated using a comprehensive panel of in vitro and in vivo assays. The studies show that lung-derived MSC are tissue-resident cells with tissue-specific properties. Lung-derived MSC have different gene expression- and cytokine patterns, higher proliferation rate, higher colony-forming capacity, and smaller size compared with bone marrow-derived MSC. Interestigly, lung-derived MSC do not have in vivo bone formation capacity. Furthermore, we demonstrate for the first time that primary lung-derived MSC are enriched in the CD90+/CD105+ mononuclear cell fraction, which have a perivascular location in situ. Additionally, we demonstrate that MSC are prominent extracellular matrix producers, and that bone marrow- and lung-derived MSC produce distinct extracellular matrix profiles. There were no significant differenses between patients with chronic and acute rejections compared with good outcome recipients regarding EDA-fibronectin expression. However, increased EDA-fibronectin expression was found in acute rejections grade A2-A3 and in biopsies from patients with infection. Finally, these studies show that tissue-resident MSC do not have an altered phenotype after BOS development and that the number of colony-forming cells i.e. MSC do not correlate with the onset of BOS. In summary, this thesis work provide novel insights of tissue-resident MSC within the lung, an important step in identifying the functional role of MSC in normal lung physiology and during disease. Hopefully in the future, this knowledge will improve clinical strategies to treat severe lung diseases such as BOS.
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| 28. |
- Rolandsson Enes, Sara, et al.
(författare)
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Primary mesenchymal stem cells in human transplanted lungs are CD90/CD105 perivascularly located tissue-resident cells
- 2014
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Ingår i: BMJ Open Respiratory Research. - : BMJ Publishing Group. - 2052-4439. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mesenchymal stem cells (MSC) have not only been implicated in the development of lung diseases, but they have also been proposed as a future cell-based therapy for lung diseases. However, the cellular identity of the primary MSC in human lung tissues has not yet been reported. This study therefore aimed to identify and characterise the ‘bona fide’ MSC in human lungs and to investigate if the MSC numbers correlate with the development of bronchiolitis obliterans syndrome in lung-transplanted patients. METHODS: Primary lung MSC were directly isolated or culture-derived from central and peripheral transbronchial biopsies of lung-transplanted patients and evaluated using a comprehensive panel of in vitro and in vivo assays. RESULTS: Primary MSC were enriched in the CD90/CD105 mononuclear cell fraction with mesenchymal progenitor frequencies of up to four colony-forming units, fibroblast/100 cells. In situ staining of lung tissues revealed that CD90/CD105 MSCs were located perivascularly. MSC were tissue-resident and exclusively donor lung-derived even in biopsies obtained from patients as long as 16 years after transplantation. Culture-derived mesenchymal stromal cells showed typical in vitro MSC properties; however, xenotransplantation into non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice showed that lung MSC readily differentiated into adipocytes and stromal tissues, but lacked significant in vivo bone formation. CONCLUSIONS: These data clearly demonstrate that primary MSC in human lung tissues are not only tissue resident but also tissue-specific. The identification and phenotypic characterisation of primary lung MSC is an important first step in identifying the role of MSC in normal lung physiology and pulmonary diseases.
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| 29. |
- Rolandsson Enes, Sara, et al.
(författare)
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Quantitative proteomic characterization of lung-MSC and bone marrow-MSC using DIA-mass spectrometry
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cells (MSC) are ideal candidates for cell therapies, due to their immune-regulatory and regenerative properties. We have previously reported that lung-derived MSC are tissue-resident cells with lung-specific properties compared to bone marrow-derived MSC. Assessing relevant molecular differences between lung-MSC and bone marrow-MSC is important, given that such differences may impact their behavior and potential therapeutic use. Here, we present an in-depth mass spectrometry (MS) based strategy to investigate the proteomes of lung-MSC and bone marrow-MSC. The MS-strategy relies on label free quantitative data-independent acquisition (DIA) analysis and targeted data analysis using a MSC specific spectral library. We identified several significantly differentially expressed proteins between lung-MSC and bone marrow-MSC within the cell layer (352 proteins) and in the conditioned medium (49 proteins). Bioinformatics analysis revealed differences in regulation of cell proliferation, which was functionally confirmed by decreasing proliferation rate through Cytochrome P450 stimulation. Our study reveals important differences within proteome and matrisome profiles between lung- and bone marrow-derived MSC that may influence their behavior and affect the clinical outcome when used for cell-therapy.
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| 30. |
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| 31. |
- Rolandsson Enes, Sara, et al.
(författare)
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Specific subsets of mesenchymal stroma cells to treat lung disorders - Finding the Holy Grail.
- 2014
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Ingår i: Pulmonary Pharmacology & Therapeutics. - : Elsevier BV. - 1522-9629 .- 1094-5539. ; 29:2, s. 93-95
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Forskningsöversikt (refereegranskat)abstract
- Accumulating studies, both in animals and human clinical trials with mesenchymal stroma cells (MSC) support the hypothesis of therapeutic effects of these cells in various disorders. However, despite success in immune-mediated disorders such as Crohns' disease, lung disorders such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary disease (IPF) treated with MSC have so far not yielded a revolutionary effect on clinical symptoms. Promising data on immunomodulatory effects in COPD have kept nourishing the research into finding specific traits of MSC beneficial in disease. A heterogeneous population of injected cells might drown a potential therapeutic role of a specific group of MSC. Thus careful analysis of MSC regarding their molecular capabilities such as delivering specific therapeutic vesicles to the environment, or plain cytokine/chemokine fingerprinting might prove useful in augmenting therapies against lung diseases.
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| 32. |
- Su, Yue, et al.
(författare)
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Mesenchymal stromal cells-derived extracellular vesicles repsogramme macrophages in ARDS models through the miR-181a-5p-PTEN-psTAT5-SOCS1 axis
- 2023
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Ingår i: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 78:6, s. 617-630
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Tidskriftsartikel (refereegranskat)abstract
- Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic.Results EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model.Conclusion miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.
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| 33. |
- Uhl, Franziska, et al.
(författare)
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Functional Role of Glycosaminoglycans in Decellularized Lung Extracellular Matrix
- 2020
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Ingår i: Acta Biomaterialia. - : Elsevier BV. - 1878-7568 .- 1742-7061. ; 102, s. 231-246
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Tidskriftsartikel (refereegranskat)abstract
- Despite progress in use of decellularized lung scaffolds in ex vivo lung bioengineering schemes, including use of gels and other materials derived from the scaffolds, the detailed composition and functional role of extracellular matrix (ECM) proteoglycans (PGs) and their glycosaminoglycan (GAG) chains remaining in decellularized lungs, is poorly understood. Using a commonly utilized detergent-based decellularization approach in human autopsy lungs resulted in disproportionate losses of GAGs with depletion of chondroitin sulfate/dermatan sulfate (CS/DS) > heparan sulfate (HS) > hyaluronic acid (HA). Specific changes in disaccharide composition of remaining GAGs were observed with disproportionate loss of NS and NS2S for HS groups and of 4S for CS/DS groups. No significant influence of smoking history, sex, time to autopsy, or age was observed in native vs. decellularized lungs. Notably, surface plasmon resonance demonstrated that GAGs remaining in decellularized lungs were unable to bind key matrix-associated growth factors FGF2, HGF, and TGFβ1. Growth of lung epithelial, pulmonary vascular, and stromal cells cultured on the surface of or embedded within gels derived from decellularized human lungs was differentially and combinatorially enhanced by replenishing specific GAGs and FGF2, HGF, and TGFβ1. In summary, lung decellularization results in loss and/or dysfunction of specific GAGs or side chains significantly affecting matrix-associated growth factor binding and lung cell metabolism. GAG and matrix-associated growth factor replenishment thus needs to be incorporated into schemes for investigations utilizing gels and other materials produced from decellularized human lungs.
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| 34. |
- Uriarte, Juan J., et al.
(författare)
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Lung bioengineering : advances and challenges in lung decellularization and recellularization
- 2018
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Ingår i: Current opinion in organ transplantation. - 1087-2418. ; 23:6, s. 673-678
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: Bioengineering the lung based on its natural extracellular matrix (ECM) offers novel opportunities to overcome the shortage of donors, to reduce chronic allograft rejections, and to improve the median survival rate of transplanted patients. During the last decade, lung tissue engineering has advanced rapidly to combine scaffolds, cells, and biologically active molecules into functional tissues to restore or improve the lung's main function, gas exchange. This review will inspect the current progress in lung bioengineering using decellularized and recellularized lung scaffolds and highlight future challenges in the field.RECENT FINDINGS: Lung decellularization and recellularization protocols have provided researchers with tools to progress toward functional lung tissue engineering. However, there is continuous evolution and refinement particularly for optimization of lung recellularization. These further the possibility of developing a transplantable bioartificial lung.SUMMARY: Bioengineering the lung using recellularized scaffolds could offer a curative option for patients with end-stage organ failure but its accomplishment remains unclear in the short-term. However, the state-of-the-art of techniques described in this review will increase our knowledge of the lung ECM and of chemical and mechanical cues which drive cell repopulation to improve the advances in lung regeneration and lung tissue engineering.
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| 35. |
- 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
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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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| 36. |
- Weiss, Daniel J., et al.
(författare)
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MSC-Based Cell Therapy for COVID-19-Associated ARDS and Classical ARDS : Comparative Perspectives
-
Ingår i: Current Stem Cell Reports. - 2198-7866.
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Forskningsöversikt (refereegranskat)abstract
- Purpose of Review: Despite no general conclusions regarding the therapeutic effect of MSCs on virus-induced acute lung injury in pre-clinical studies, a significant number of clinical trials using MSC-based treatment for COVID-19-associated ARDS were initiated during the global pandemic. Here, we aimed to discuss differences and similarities in clinical trials using MSC-based treatments for classical ARDS and COVID-19-associated ARDS and to raise some future perspectives. Recent Findings: Several pre-clinical studies have demonstrated that MSC treatment may not be a good treatment option for virus infections because MSCs themselves are susceptible to the virus. However, MSCs lack expression of the angiotensin-converting enzyme 2 (ACE2) receptor, suggesting that MSCs are not likely to be infected by the COVID-19 virus. Interestingly, recent meta-analyses demonstrated that an improved survival rate in patients with COVID-19-associated ARDS treated with MSCs was obtained in 24 out of 26 completed clinical trials. Summary: This review provides comparative perspectives on MSC-based therapy for COVID-19-associated ARDS and classical ARDS.
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| 37. |
- Weiss, Daniel J, et al.
(författare)
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MSCs interaction with the host lung microenvironment : An overlooked aspect?
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Mesenchymal stromal cells (MSCs) were identified more than 50 years ago, and research advances have promoted the translation of pre-clinical studies into clinical settings in several diseases. However, we are only starting to uncover the local factors that regulate cell phenotype, cell function, and cell viability across tissues following administration in different diseases. Advances in pre-clinical and translational studies suggest that the host environment, especially inflammatory active environments, plays a significant role in directing the infused MSCs towards different phenotypes with different functions. This can significantly effect their therapeutic efficacy. One way to study this interaction between the host environment and the infused cells is to expose MSCs ex vivo to patient samples such as serum or bronchoalveolar lavage fluid. Using this approach, it has been demonstrated that MSCs are very sensitive to different host factors such as pathogens, inflammatory cytokines, and extra cellular matrix properties. By understanding how different local host factors effect MSC function it will open possibilities to select specific patient sub-groups that are more likely to respond to this type of treatment and will also open possibilities to prime the local host environment to increase viability and to enrich for a specific MSC phenotype. Here, we aim to review the current understanding of the interaction of MSCs with the host microenvironment. To narrow the scope of this mini review, the focus will be on the pulmonary microenvironment, with a specific focus on the diseases acute respiratory distress syndrome (ARDS) and cystic fibrosis (CF).
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| 38. |
- Weitoft, Maria, et al.
(författare)
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Plasma proteome changes linked to late phase response after inhaled allergen challenge in asthmatics
- 2022
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: A subset of individuals with allergic asthma develops a late phase response (LPR) to inhaled allergens, which is characterized by a prolonged airway obstruction, airway inflammation and airway hyperresponsiveness. The aim of this study was to identify changes in the plasma proteome and circulating hematopoietic progenitor cells associated with the LPR following inhaled allergen challenge. Methods: Serial plasma samples from asthmatics undergoing inhaled allergen challenge were analyzed by mass spectrometry and immunosorbent assays. Peripheral blood mononuclear cells were analyzed by flow cytometry. Mass spectrometry data were analyzed using a linear regression to model the relationship between airway obstruction during the LPR and plasma proteome changes. Data from immunosorbent assays were analyzed using linear mixed models. Results: Out of 396 proteins quantified in plasma, 150 showed a statistically significant change 23 h post allergen challenge. Among the most upregulated proteins were three protease inhibitors: alpha-1-antitrypsin, alpha-1-antichymotrypsin and plasma serine protease inhibitor. Altered levels of 13 proteins were associated with the LPR, including increased factor XIII A and decreased von Willebrand factor. No relationship was found between the LPR and changes in the proportions of classical, intermediate, and non-classical monocytes. Conclusions: Allergic reactions to inhaled allergens in asthmatic subjects were associated with changes in a large proportion of the measured plasma proteome, whereof protease inhibitors showed the largest changes, likely to influence the inflammatory response. Many of the proteins altered in relation to the LPR are associated with coagulation, highlighting potential mechanistic targets for future treatments of type-2 asthma.
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| 39. |
- Westergren-Thorsson, Gunilla, et al.
(författare)
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Challenges and opportunities for regenerating lung tissue using three-dimensional lung models
- 2022
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Ingår i: 3D lung models for regenerating lung tissue. - 9780323908719 ; , s. 239-241
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Bokkapitel (refereegranskat)abstract
- Lung transplantation is currently the only option for patients with end-stage respiratory diseases, but owing to various complications and adverse effects of the treatment in combination with the increasing demand for and limited access to donor organs, new strategies are needed. Recent advances in materials science, culture techniques, cell-phenotyping and isolation techniques, bioreactor engineering, and imaging techniques have opened up new possibilities for generating advanced three-dimensional lung models. The lung is a complex organ to rebuild, consisting of more than 40 different cell types working together to create a functional unit that allows for proper gas exchange and protection against the external environment. However, it is well known that the cells do not work alone. It was long thought that the only function of the extracellular matrix (ECM) was to provide the organ and cells with structural support, but we now know that the ECM plays a much more vital role. Despite this knowledge, the majority of studies are still performed by using traditional two-dimensional (2D) cultures on plastic. There are, of course, occasions when 2D cultures are necessary; however, it is important to remember that essential features, including orientation, mechanical properties, and cell-cell and cell-matrix interactions, are missing. These are important properties that will most likely affect the final results and the possibility of translating in vitro findings into in vivo models.
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| 40. |
- Westergren-Thorsson, Gunilla, et al.
(författare)
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Preface
- 2022
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Ingår i: 3D Lung Models for Regenerating Lung Tissue. - 9780323908719 - 9780323908726
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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