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Research into newly found stem cells that can trigger a repair mechanism in damaged lungs.
Researchers have discovered stem cells in the lungs that can repair damaged air sacks. Activating the mechanism can lead to new therapies for severe conditions like chronic obstructive pulmonary disease (COPD).
In 10 seconds? Scientists are studying how to trigger special stem cells found in our lungs to repair tissue, potentially reversing the damage caused by currently incurable COPD.
How did they found those stem cells? Researchers discovered alveolar epithelial progenitor (AEP) cells in the lungs of mice. They found that after infecting the animals with flu, AEP cells quickly expanded and regenerated damaged air-sacs known as alveoli. They then discovered similar stem cells in humans, which make animal studies very valuable to us. Read the research paper
What will these studies lead to? We hope to be able to manipulate this mechanism to help COPD-patients, who have difficulties with breathing. Switching on the process would make the stem cells repair the alveoli, crucial to the oxygen supply of the body.
So, how does the process work? This part of the lung is wrapped in a film of so-called epithelial cells. The same type of cells are present elsewhere in the body protecting cavities. But, whereas in the intestines they renew around every five days, in the lungs renewal only starts when stem cells kick in upon injury. Being able to flick the swith would speed up the healing process, making people breathe more easily.
Is there another way? Scientists have grown epthelial cells in the lab to experiment with artificial scaffolds in order to speed up tissue growth. They are also studying the effects of proteins secreted by nasal fibroblast cells - as such cells play a key role in wound healing.
So, would this be a cure for COPD? These are only the first, but promising steps. Epithelial cells are vital for healthy airway functions, so the discovery could lead to therapies not only for COPD but for cystic fibrosis as well. And as the respiratory and vascular systems are closely linked, scientists want to use the method for blood vessel regeneration.
Why do we need to talk about COPD?
Chronic obstructive pulmonary disease is expected to become the 3rd leading cause of death worldwide by 2030, with over 60 million people living with the condition around the globe.
COPD - which is mainly caused by smoking - gets worse over time and has no cure, but can be managed by the right treatment.
It is accompanied by lung damage in the alveoli, that results in less oxygen reaching parts of the body, with less carbon dioxide being exhaled.
This results in symptoms such as shortness of breath, coughing, mucus production and wheezing.
Abstract: Functional tissue regeneration is required for the restoration of normal organ homeostasis after severe injury. Some organs, such as the intestine, harbour active stem cells throughout homeostasis and regeneration; more quiescent organs, such as the lung, often contain facultative progenitor cells that are recruited after injury to participate in regeneration. Here we show that a Wnt-responsive alveolar epithelial progenitor (AEP) lineage within the alveolar type 2 cell population acts as a major facultative progenitor cell in the distal lung. AEPs are a stable lineage during alveolar homeostasis but expand rapidly to regenerate a large proportion of the alveolar epithelium after acute lung injury. AEPs exhibit a distinct transcriptome, epigenome and functional phenotype and respond specifically to Wnt and Fgf signalling. In contrast to other proposed lung progenitor cells, human AEPs can be directly isolated by expression of the conserved cell surface marker TM4SF1, and act as functional human alveolar epithelial progenitor cells in 3D organoids. Our results identify the AEP lineage as an evolutionarily conserved alveolar progenitor that represents a new target for human lung regeneration strategies.
Pub.: 01 Mar '18, Pinned: 13 Jun '18
Abstract: Increasing evidence suggests that human antigen R (HuR) is involved in the epithelial-mesenchymal transition (EMT) process of several diseases. However, the role of HuR in EMT in the airway epithelial cells of patients with COPD remains unclear.BEAS-2B cells were cultured and treated with 3%CSE. Western blotting, RT-PCR and immunofluoresence were used to detect the expression of HuR, ZEB-1. RNAi was used to suppress HuR expression. Then knockdown of HuR, RT-PCR and Western blotting showed that with siHuR-1 and siHuR-3, clear suppression of HuR expression was confirmed. We chose siHuR-3, the most effective one, to proceed with subsequent experiments. Immunofluorescence analysis, western blotting were used to detect the expression of E-cadherin, vimentin, ZEB-1 and HuR.We show that more HuR expression is enhanced in the airways epithelium of smokers with or without COPD than controls (nonsmoker non-COPD patients). However, there was no definite correlation between HuR expression and FEV1%. Further study reveals that knockdown of HuR significantly increases the apoptosis of BEAS-2B cells and down-regulates ZEB-1 expression.EMT is partially enhanced through the HuR-binding proteins and its post-transcriptional regulation role in airway epithelium in COPD.
Pub.: 04 Jun '18, Pinned: 13 Jun '18
Abstract: Chronic obstructive pulmonary disease (COPD) is a critical condition with high morbidity and mortality. Although several medications are available, there are no definite treatments. However, recent advances in the understanding of stem and progenitor cells in the lung, and molecular changes during re-alveolization after pneumonectomy, have made it possible to envisage the regeneration of damaged lungs. With this background, numerous studies of stem cells and various stimulatory molecules have been undertaken, to try and regenerate destroyed lungs in animal models of COPD. Both the cell and drug therapies show promising results. However, in contrast to the successes in laboratories, no clinical trials have exhibited satisfactory efficacy, although they were generally safe and tolerable. In this article, we review the previous experimental and clinical trials, and summarize the recent advances in lung regeneration therapy for COPD. Furthermore, we discuss the current limitations and future perspectives of this emerging field.
Pub.: 26 Jan '17, Pinned: 13 Jun '18
Abstract: COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
Pub.: 15 Apr '18, Pinned: 13 Jun '18
Abstract: Cystic fibrosis is a genetic disease caused by mutations in the CFTR gene, whereas chronic obstructive pulmonary disease (COPD) is mainly caused by environmental factors (mostly cigarette smoking) on a genetically susceptible background. Although the etiology and pathogenesis of these diseases are different, both are associated with progressive airflow obstruction, airway neutrophilic inflammation, and recurrent exacerbations, suggesting common mechanisms. The airway epithelium plays a crucial role in maintaining normal airway functions. Major molecular and morphologic changes occur in the airway epithelium in both CF and COPD, and growing evidence suggests that airway epithelial dysfunction is involved in disease initiation and progression in both diseases. Structural and functional abnormalities in both airway and alveolar epithelium have a relevant impact on alteration of host defences, immune/inflammatory response, and the repair process leading to progressive lung damage and impaired lung function. In this review, we address the evidence for a critical role of dysfunctional airway epithelial cells in chronic airway inflammation and remodelling in CF and COPD, highlighting the common mechanisms involved in the epithelial dysfunction as well as the similarities and differences of the two diseases.
Pub.: 01 Jun '18, Pinned: 13 Jun '18
Abstract: In healthy subjects, the respiratory epithelium forms a continuous lining to the airways and to the environment, and plays a unique role as a barrier against external deleterious agents to protect the airways from the insults. In respiratory diseases such as cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), chronic bronchitis, or asthma, the airway epithelium is frequently remodeled and injured, leading to the impairment of its defense functions. The rapid restoration of the epithelial barrier is crucial for these patients. The complete regeneration of the airway epithelium is a complex phenomenon, including not only the epithelial wound repair but also the epithelial differentiation to reconstitute a fully well differentiated and functional epithelium. The regeneration implies two partners: the epithelial stem/progenitor cells and factors able to regulate this process. Among these factors, epithelial cells-extracellular matrix (ECM) interactions play a crucial role. The secretion of a provisional ECM, the cell-ECM relationships through epithelial receptors, and the remodeling of the ECM by proteases (mainly matrix metalloproteinases) contribute not only to airway epithelial repair by modulating epithelial cell migration and proliferation, but also to the differentiation of repairing cells leading to the complete restoration of the wounded epithelium. A better characterization of resident stem cells and of effectors of the regeneration process is an essential prerequisite to propose new regenerative therapeutics to patients suffering from infectious/inflammatory respiratory diseases.
Pub.: 08 Aug '08, Pinned: 13 Jun '18
Abstract: Despite an efficient defence system, the airway surface epithelium, in permanent contact with the external milieu, is frequently injured by inhaled pollutants, microorganisms and viruses. The response of the airway surface epithelium to an acute injury includes a succession of cellular events varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even to complete denudation of the basement membrane. The epithelium has then to repair and regenerate to restore its functions, through several mechanisms including basal cell spreading and migration, followed by proliferation and differentiation of epithelial cells. The cellular and molecular factors involved in wound repair and epithelial regeneration are closely interacting and imply extracellular matrix proteins, matrix metalloproteinases (MMPs) and their inhibitors as well as cytokines and growth factors secreted by airway epithelial and mesenchymal cells. The development of in vitro and in vivo models of airway epithelium wound repair allowed the study of the spatio-temporal modulation of these factors during the different steps of epithelial repair and regeneration. In this context, several studies have demonstrated that the matrix and secretory environment are markedly involved in these mechanisms and that their dysregulation may induce remodelling of the airway mucosa. A better knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to regenerative therapeutics allowing the reconstitution of a functional airway epithelium in numerous respiratory diseases such as asthma, chronic obstructive pulmonary diseases, cystic fibrosis and bronchiolitis.
Pub.: 06 Dec '05, Pinned: 13 Jun '18
Abstract: Understanding the mechanisms underlying the process of regeneration and repair of airway epithelial structures demands close characterization of the associated cellular and molecular events. The choice of an animal model system to study these processes and the role of lung stem cells is debatable since ideally the chosen animal model should offer a valid comparison with the human lung. Species differences may include the complex three-dimensional lung structures, cellular composition of the lung airway as well as transcriptional control of the molecular events in response to airway epithelium regeneration, and repair following injury. In this paper, we discuss issues related to the study of the lung repair and regeneration including the role of putative stem cells in small- and large-animal models. At the end of this paper, the author discuss the potential for using sheep as a model which can help bridge the gap between small-animal model systems and humans.
Pub.: 11 Oct '12, Pinned: 13 Jun '18
Abstract: In chronic obstructive pulmonary disease (COPD), exacerbations are generally associated with several causes, including pollutants, viruses, bacteria that are responsible for an excess of inflammatory mediators, and proinflammatory cytokines released by activated epithelial and inflammatory cells. The normal response of the airway surface epithelium to injury includes a succession of cellular events, varying from the loss of the surface epithelium integrity to partial shedding of the epithelium or even complete denudation of the basement membrane. The epithelium then has to repair and regenerate to restore its functions, through several mechanisms, including basal cell spreading and migration, followed by proliferation and differentiation of epithelial cells. In COPD, the remodeling of the airway epithelium, such as squamous metaplasia and mucous hyperplasia that occur during injury, may considerably disturb the innate immune functions of the airway epithelium. In vitro and in vivo models of airway epithelial wound repair and regeneration allow the study of the spatiotemporal modulation of cellular and molecular interaction factors-namely, the proinflammatory cytokines, the matrix metalloproteinases and their inhibitors, and the intercellular adhesion molecules. These factors may be markedly altered during exacerbation periods of COPD and their dysregulation may induce remodeling of the airway mucosa and a leakiness of the airway surface epithelium. More knowledge of the mechanisms involved in airway epithelium regeneration may pave the way to cytoprotective and regenerative therapeutics, allowing the reconstitution of a functional, well-differentiated airway epithelium in COPD.
Pub.: 27 Oct '06, Pinned: 13 Jun '18