225 research outputs found
Stem cell-based therapy for lung disease
Get PDFThis book presents state-of-the-art pre-clinical models and clinical applications of stem-cell-based therapies applied to different lung diseases, with a special focus on the translation of bench data into clinical studies. Starting with the assumption that abnormal lung tissue repair and regeneration has emerged as the driving force underlying pathogenesis and progression in many lung diseases, it sheds new light on the potential of stem/stromal cells as drivers of repair and sources of reparative factors in the lung. The first part of the book offers an overview of stem cell types and mechanisms involved in lung development, homeostasis, repair and regeneration, and reveals the crucial role of the extracellular matrix within the lung microenvironment. In the second part, leading experts present the latest pre-clinical evidence and clinical applications of stem-cell-based therapies in a wide variety of lung diseases, ranging from COPD and lung fibrosis to other rare lung diseases. The last section discusses stem cell delivery systems and devices, such as aerosolised spray application. This book appeals to pneumologists, stem cell and matrix biologists, as well as bioengeneers with a special interest in regenerative medicine applied to pulmonary diseases.</p
Challenges and opportunities for the future of stem cell therapy for lung diseases
Get PDFIn this era of striving for personalized medicine approaches for complex diseases, preclinical studies have excited the field through their demonstration of the promise of stem cell therapy for the treatment of various lung diseases; with the most beneficial effects of stem cell-based strategies in preclinical settings originating from their antimicrobial, anti-inflammatory, and immunomodulatory properties. Although many lung disorders involve an inflammatory component, effective stem cell therapy in patients has not been realized yet for the majority of lung diseases and there are still multiple hurdles to be overcome. While beneficial effects have been realized in clinical studies of CF, results from clinical studies in other lung diseases have been disappointing to date. We discuss the questions that should be addressed before considering administration of stem cells or their derivatives in a phase I studies. We should prevent stem cell tourism, where cell-based therapies are being marketed to extremely vulnerable patient populations and their caregivers. Unproven and often unsafe stem cell treatment practices can mislead patients into participating in often very expensive, unregulated, unethical, and unsafe treatments, which are not covered by insurance. Here, the education of patients, caregivers and of pulmonologists who are not familiar with the stem cell field will be of great value.</p
miR-223 : a key regulator in the innate immune response in asthma and COPD
Get PDFAsthma and Chronic Obstructive Pulmonary Disease (COPD) are chronic obstructive respiratory diseases characterized by airway obstruction, inflammation, and remodeling. Recent findings indicate the importance of microRNAs (miRNAs) in the regulation of pathological processes involved in both diseases. MiRNAs have been implicated in a wide array of biological processes, such as inflammation, cell proliferation, differentiation, and death. MiR-223 is one of the miRNAs that is thought to play a role in obstructive lung disease as altered expression levels have been observed in both asthma and COPD. MiR-223 is a hematopoietic cell-derived miRNA that plays a role in regulation of monocyte-macrophage differentiation, neutrophil recruitment, and pro-inflammatory responses and that can be transferred to non-myeloid cells via extracellular vesicles or lipoproteins. In this translational review, we highlight the role of miR-223 in obstructive respiratory diseases, focusing on expression data in clinical samples of asthma and COPD, in vivo experiments in mouse models and in vitro functional studies. Furthermore, we provide an overview of the mechanisms by which miR-223 regulates gene expression. We specifically focus on immune cell development and activation and involvement in immune responses, which are important in asthma and COPD. Collectively, this review demonstrates the importance of miR-223 in obstructive respiratory diseases and explores its therapeutic potential in the pathogenesis of asthma and COPD
Effects of cigarette smoking on SARS-CoV-2 receptor ACE2 expression in the respiratory epithelium(dagger)
Get PDFDue to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, the world is currently facing high morbidity and mortality rates as well as severe disruption to normal societal and social structures. SARS-CoV-2 uses the ACE2 receptor for cellular entry. In a recent publication of The Journal of Pathology, Liu and coworkers highlight the effects of cigarette smoking on ACE2 expression in the respiratory epithelium. The authors studied the effects of acute cigarette smoke exposure in a murine model and confirmed their findings in human lung tissues and gene expression datasets. Their findings demonstrate that cigarette smoking increases ACE2 expression specifically at the apical surface of the airway epithelium. Smoking cessation resulted in lower ACE2 expression, with implications for attenuating the risk of transmission of the virus. The role of ACE2 expression in the development of COVID-19 symptoms is still under investigation, with conflicting results from experimental models on the role of ACE2 expression in SARS-CoV-2-induced lung injury. In this commentary, we highlight the implications and limitations of the study of Liu et al as well as future therapeutic strategies directed towards ACE2. (c) 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland
Mesenchymal Stromal Cells to Regenerate Emphysema:On the Horizon?
Get PDFMesenchymal stem or stromal cells (MSCs) are multipotent cells that play a pivotal role in various phases of lung development and lung homeostasis, and potentially also lung regeneration. MSCs do not only self-renew and differentiate into renew tissues, but also have anti-inflammatory and paracrine properties to reduce damage and to support tissue regeneration, constituting a promising cell-based treatment strategy for the repair of damaged alveolar tissue in emphysema. This review discusses the current state of the art regarding the potential of MSCs for the treatment of emphysema. The optimism regarding this treatment strategy is supported by promising results from animal models. Still, there are considerable challenges before effective stem cell treatment can be realized in emphysema patients. It is difficult to draw definitive conclusions from the available animal studies, as different models, dosage protocols, administration routes, and sources of MSCs have been used with different measures of effectiveness. Moreover, the regrowth potential of differentiated tissues and organs differs between species. Essential questions about MSC engraftment, retention, and survival have not been sufficiently addressed in a systematic manner. Few human studies have investigated MSC treatment for chronic obstructive pulmonary disease, demonstrating short-term safety but no convincing benefits on clinical outcomes. Possible explanations for the lack of beneficial effects on clinical outcomes could be the source (bone marrow), route, dosage, frequency of administration, and delivery (lack of a bioactive scaffold). This review will provide a comprehensive overview of the (pre)clinical studies on MSC effects in emphysema and discuss the current challenges regarding the optimal use of MSCs for cell-based therapies
Current perspectives on the role of interleukin-1 signalling in the pathogenesis of asthma and COPD
Get PDFAsthma and chronic obstructive pulmonary disease (COPD) cause significant morbidity and mortality worldwide. In the context of disease pathogenesis, both asthma and COPD involve chronic inflammation of the lung and are characterised by the abnormal release of inflammatory cytokines, dysregulated immune cell activity and remodelling of the airways. To date, current treatments still only manage symptoms and do not reverse the primary disease processes. In recent work, interleukin (IL)-1α and IL-1β have been suggested to play important roles in both asthma and COPD. In this review, we summarise overwhelming pre-clinical evidence for dysregulated signalling of IL-1α and IL-1β contributing to disease pathogenesis and discuss the paradox of IL-1 therapeutic studies in asthma and COPD. This is particularly important given recent completed and ongoing clinical trials with IL-1 biologics that have had varying degrees of failure and success as therapeutics for disease modification in asthma and COPD
Dysregulated cross-talk between alveolar epithelial cells and stromal cells in idiopathic pulmonary fibrosis reduces epithelial regenerative capacity
Get PDFIn idiopathic pulmonary fibrosis (IPF) constant epithelial micro-injury and aberrant interactions within the stromal micro-environment lead to abnormal alveolar repair and fibrosis. We hypothesized that alveolar epithelial regenerative responses in IPF are impaired due to disturbed crosstalk between epithelial cells and their stromal niche. We established organoid cultures from unfractionated suspensions and isolated EpCAM+ cells from distal lung tissue of patients with and without IPF. We observed significantly more organoids being formed from unfractionated suspensions compared to isolated EpCAM+ cell cultures, indicating the presence of supportive cells in the unfractionated suspensions. Importantly, lower organoid numbers were observed in unfractionated cultures from IPF lungs compared to non-IPF lungs. This difference was not found when comparing organoid formation from isolated EpCAM+ cells alone between IPF and non-IPF groups, suggesting that crosstalk between the supportive population and epithelial cells is impaired in lungs from IPF patients. Additionally, organoids grown from IPF lung-derived cells were larger in size compared to those from non-IPF lungs in both unfractionated and EpCAM+ cultures, indicating an intrinsic abnormality in epithelial progenitors from IPF lungs. Together, our observations suggest that dysregulated crosstalk between alveolar progenitor cells and the stromal niche affects the regenerative capacity, potentially contributing to alveolar impairment in IPF
Development of a Widely Accessible, Advanced Large-Scale Microfluidic Airway-on-Chip
Get PDFOn-chip microfluidics are advanced in vitro models that simulate lung tissue's native 3D environment more closely than static 2D models to investigate the complex lung architecture and multifactorial processes that lead to pulmonary disease. Current microfluidic systems can be restrictive in the quantities of biological sample that can be retrieved from a single micro-channel, such as RNA, protein, and supernatant. Here, we describe a newly developed large-scale airway-on-chip model that employs a surface area for a cell culture wider than that in currently available systems. This enables the collection of samples comparable in volume to traditional cell culture systems, making the device applicable to any workflow utilizing these static systems (RNA isolation, ELISA, etc.). With our construction method, this larger culture area allows for easier handling, the potential for a wide range of exposures, as well as the collection of low-quantity samples (e.g., volatiles or mitochondrial RNA). The model consists of two large polydimethylsiloxane (PDMS) cell culture chambers under an independent flow of medium or air, separated by a semi-permeable polyethylene (PET) cell culture membrane (23 μm thick, 0.4 μm pore size). Each chamber carries a 5 × 18 mm, 90 mm2 (92 mm2 with tapered chamber inlets) surface area that can contain up to 1-2 × 104 adherent structural lung cells and can be utilized for close contact co-culture studies of different lung cell types, including airway epithelial cells, fibroblasts, smooth muscle cells, and endothelial cells. The parallel bi-chambered design of the chip allows for epithelial cells to be cultured at the air-liquid interface (ALI) and differentiation into a dense, multi-layered, pseudostratified epithelium under biological flow rates. This millifluidic airway-on-chip advances the field by providing a readily reproducible, easily adjustable, and cost-effective large-scale fluidic 3D airway cell culture platform.</p
Mitochondria:at the crossroads of regulating lung epithelial cell function in chronic obstructive pulmonary disease
Get PDFDisturbances in mitochondrial structure and function in lung epithelial cells have been implicated in the pathogenesis of various lung diseases, including chronic obstructive pulmonary disease (COPD). Such disturbances affect not only cellular energy metabolism but also alter a range of indispensable cellular homeostatic functions in which mitochondria are known to be involved. These range from cellular differentiation, cell death pathways, and cellular remodeling to physical barrier function and innate immunity. all of which are known to be impacted by exposure to cigarette smoke and have been linked to COPD pathogenesis. Next to their well-established role as the first physical frontline against external insults, lung epithelial cells are immunologically active. Malfunctioning epithelial cells with defective mitochondria are unable to maintain homeostasis and respond adequately to further stress or injury, which may ultimately shape the phenotype of lung diseases. In this review, we provide a comprehensive overview of the impact of cigarette smoke on the development of mitochondrial dysfunction in the lung epithelium and highlight the consequences for cell function, innate immune responses, epithelial remodeling, and epithelial barrier function in COPD. We also discuss the applicability and potential therapeutic value of recently proposed strategies for the restoration of mitochondrial function in the treatment of COPD
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