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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.

Purpose of Review Mesenchymal stromal cell (MSC)–based therapies provide a platform for new therapeutic strategies in lung diseases. This review provides an overview of the current status of the field, along with some of the challenges ahead including better understanding of MSC actions in different lung diseases, personalized approaches to select patients most likely to benefit, and the growing problem of stem cell tourism. Recent Findings A newly evolving concept suggests that MSCs shape their immunomodulatory actions depending on the environment they encounter. Furthermore, in some models, it appears that dying or dead cells may contribute to the therapeutic efficacy by activating the host response. Summary Despite many pre-clinical studies demonstrating that MSCs can be used to treat lung disorders, clinical trials have failed to show improved outcome. Understanding the complex interaction between MSCs and the host microenvironment is likely to be an important area for enhancing the efficacy of MSC-based cell therapies.

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. STATEMENT OF SIGNIFICANCE: 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. In the current studies, we demonstrate that glycosaminoglycans (GAGs) are significantly depleted during decellularization and those that remain are dysfunctional and unable to bind matrix-associated growth factors critical for cell growth and differentiation. Systematically repleting GAGs and matrix-associated growth factors to gels derived from decellularized human lung significantly and differentially affects cell growth. These studies highlight the importance of considering GAGs in decellularized lungs and their derivatives.

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., Highlights of basic and translational science presented at #ERSCongress 2019 summarising latest research on the lung cell atlas, lung infections, early origins of lung disease and the importance of metabolic alterations in the lung http://bit.ly/2UbdBs4

At the European Respiratory Society (ERS) International Congress in Paris (France) in 2018, the Early Career Members Committee (ECMC) postulated the idea of providing an incentive for ambitious and successful Early Career Members (ECMs) through granting an ECM award. The ECMC forwarded the concept to the ERS Executive Committee. ECM representatives of each assembly discussed the nomination of an ECM within each assembly. Based on their curriculum vitae and involvement within ERS, the nominees were ranked, and Lies Lahousse became the laureate of the first ERS Early Career Member Award (figure 1). Two ECMs (T. Janssens and J. De Brandt) visited Prof. Lahousse in Ghent (Belgium) to interview her., All you need to know about @LiesLahousse, first ECM to be granted the Early Career Member Award; #LSC2020; the newly elected assembly representatives for @EarlyCareerERS; and new @EuroRespSoc fellowship opportunities http://bit.ly/2OTgQlo

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 understand how the disease microenvironment influences MSC activation and therapeutic actions, in addition to the need for a patient-stratification approach.

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.

BackgroundDespite increased interest in mesenchymal stromal cell (MSC)-based cell therapies for acute respiratory distress syndrome (ARDS), clinical investigations have not yet been successful and our understanding of the potential in vivo mechanisms of MSC actions in ARDS remains limited. ARDS is driven by an acute severe innate immune dysregulation, often characterised by inflammation, coagulation and cell injury. How this inflammatory microenvironment influences MSC functions remains to be determined.AimThe aim of this study was to comparatively assess how the inflammatory environment present in ARDS lungs versus the lung environment present in healthy volunteers alters MSC behaviour.MethodsClinical-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 human leukocyte antigen expression, and activation of coagulation and complement pathways.ResultsPro-inflammatory, pro-coagulant and major histocompatibility complex (self-recognition) related gene expression was markedly upregulated in hMSCs exposed ex vivo to BALF obtained from healthy volunteers. These changes were less apparent and often opposite in hMSCs exposed to ARDS BALF samples.ConclusionThese data provide new insights into how hMSCs behave in healthy versus inflamed lung environments, and strongly suggest that the inflamed environment in ARDS induces hMSC responses that are potentially beneficial for cell survival and actions. This further highlights the need to understand how different disease environments affect hMSC functions.

Recent advances in cell based therapies for lung diseases and critical illnesses offer significant promise. Despite encouraging preclinical results, the translation of efficacy to the clinical settings have not been successful. One of the possible reasons for this is the lack of understanding of the complex interaction between mesenchymal stromal cells (MSCs) and the host environment. Other challenges for MSC cell therapies include cell sources, dosing, disease target, donor variability, and cell product manufacturing. Here we provide an overview on advances and current issues with a focus on MSC-based cell therapies for inflammatory acute respiratory distress syndrome varieties and other inflammatory lung diseases.

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., This workshop report discusses recent advances in cell therapy and bioengineering approaches for repair and regeneration of diseased lungs https://bit.ly/2DqA8eu

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 were compared with effects of BALF collected from healthy volunteers. CF BALF samples that 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, antimicrobial 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.

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.

Highlights • Cardiovascular autonomic nerve function (i.e. E/I ratio) deteriorates over time in type 1 diabetes. • HSP27, MIF and PAI-1 concentrations do not correlate with cardiovascular autonomic nerve function. • The change in HbA1c correlates negatively with the change in E/I over time. • Higher HbA1c is associated with worse cardiovascular autonomic nerve function., 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.

Advances in mesenchymal stem (stromal) cell (MSC)-based therapies provides a platform for development of new therapeutic approaches for severe inflammatory lung disorders. However, despite increasing numbers of preclinical studies demonstrating efficacy, clinical trials of MSCs in lung diseases while uniformly demonstrating safety, have not demonstrated efficacy. We hypothesize that the specific inflammatory environments present in ARDS and CF patients will induce different anti-inflammatory MSC actions that play critical roles in mitigating lung injury. Human MSCs were exposed to bronchoalveolar lavage fluid (BALF) obtained from patients with ARDS and CF. Following exposures, MSCs and/or conditioned medium were assessed for e.g. levels of immunomodulatory cytokines, gene expression profiles, cytotoxicity, and immunomodulatory functions. MSCs exposed to BALF samples obtained from patients with ARDS and CF activated different inflammatory responses. Increased levels of IL-1RN and IL-6 mRNA was observed in MSCs exposed to ARDS BALF, whereas MSCs exposed to CF BALF demonstrated decreased levels. Gene expression data revealed significant different profiles between MSCs exposed to ARDS and CF BALF. Notably, MSCs exposed to a sub-population of the CF BALF samples were found to have profound killing effects, an apoptotic pathway activated by Aspergillus. By inactivating Gliotoxin, the main fungal toxin, MSCs were protected from cell death. Our data suggest that MSCs exposed to clinical BALF samples obtained from patients with ARDS and CF can activate different inflammatory responses that may have differential effect on mitigating lung injuries.

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.

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.

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.

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. (Less)

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).

Background: The mesenchymal stromal cells (MSC) are potent candidates for cell therapies, due to their immune-regulatory and regenerative properties. In most clinical trials bone marrow-derived MSC have been used, also for treatment of various pulmonary diseases. Bone marrow-derived MSC play an important role within the bone marrow, by providing and maintaining a functioning niche for the hematopoiesis. The functional role of lung-resident MSC, on the other hand, is still unknown. Exploring the proteins produced by lung-derived MSC might improve our understanding of the functional role of MSC within the lung. Therefore, we aimed to characterize the proteins produced by lung-derived MSC and to compare those findings to the proteins produced by MSC isolated from bone marrow. Methods: Proteins within the cell-layer and the conditioned medium of MSC isolated from lung biopsies and bone marrow aspirates were characterized using mass spectrometry-based quantitative proteomics. Results: Our results indicate that MSC isolated from lung biopsies and bone marrow aspirates are prominent producers of extracellular matrix proteins. Furthermore, these analyses revealed differences between lung- and bone marrow-derived MSC, both regarding proteins identified in the cell layer and within the conditioned medium. Conclusions: Lung-derived MSC are prominent extracellular matrix producers, and our results indicate that lung- and bone marrow-derived MSC produce different protein profiles.

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.

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. This proof of concept study suggest that different lung inflammatory environments potentially can alter hMSC behaviors. Further identification of these interactions and the driving mechanisms may influence clinical use of MSCs for treating lung diseases.