Comparative single-cell analysis reveals IFN-γ as a driver of respiratory sequelae post COVID-19 (preprint)

Post-acute sequelae of SARS-CoV-2 infection (PASC) represents an urgent public health challenge, with its impact resonating in over 60 million individuals globally. While a growing body of evidence suggests that dysregulated immune reactions may be linked with PASC symptoms, most investigations have primarily centered around blood studies, with few focusing on samples derived from post-COVID affected tissues. Further, clinical studies alone often provide correlative insights rather than causal relationships. Thus, it is essential to compare clinical samples with relevant animal models and conduct functional experiments to truly understand the etiology of PASC. In this study, we have made comprehensive comparisons between bronchoalveolar lavage fluid (BAL) single-cell RNA sequencing (scRNAseq) data derived from clinical PASC samples and relevant PASC mouse models. This revealed a strong pro-fibrotic monocyte-derived macrophage response in respiratory PASC (R-PASC) in both humans and mice, and abnormal interactions between pulmonary macrophages and respiratory resident T cells. IFN-g emerged as a key node mediating the immune anomalies in R-PASC. Strikingly, neutralizing IFN-g post the resolution of acute infection reduced lung inflammation, tissue fibrosis, and improved pulmonary gas-exchange function in two mouse models of R-PASC. Our study underscores the importance of performing comparative analysis to understand the root cause of PASC for developing effective therapies.

Disease trajectories in hospitalized COVID-19 patients are predicted by clinical and peripheral blood signatures representing distinct lung pathologies. (preprint)

Linking clinical biomarkers and lung pathology still is necessary to understand COVID-19 pathogenesis and the basis of progression to lethal outcomes. Resolving these knowledge gaps enables optimal treatment approaches of severe COVID-19. We present an integrated analysis of longitudinal clinical parameters, blood biomarkers and lung pathology in COVID-19 patients from the Brazilian Amazon. We identified core signatures differentiating severe recovered patients and fatal cases with distinct disease trajectories. Progression to early death was characterized by rapid and intense endothelial and myeloid activation, presence of thrombi, mostly driven by SARS-CoV-2 + macrophages. Progression to late death was associated with systemic cytotoxicity, interferon and Th17 signatures and fibrosis, apoptosis, and abundant SARS-CoV-2 + epithelial cells in the lung. Progression to recovery was associated with pro-lymphogenic and Th2-mediated responses. Integration of antemortem clinical and blood biomarkers with post-mortem lung-specific signatures defined predictors of disease progression, identifying potential targets for more precise and effective treatments.

Self-assembly vascularized human cardiac organoids model cardiac diseases in petri dishes and in mice (preprint)

In this study, we generated self-assembly cardiac organoids (COs) from human pluripotent stem cells by dual-phase modulation of Wnt/{beta}-catenin pathway, utilizing CHIR99021 and IWR-1-endo. The resulting COs exhibited a diverse array of cardiac-specific cell lineages, cardiac cavity-like structures and demonstrated the capacity of spontaneous beating and vascularization in vitro. We further employed these complex and functional COs to replicate conditions akin to human myocardial infarction and SARS-CoV-2 induced fibrosis. These models accurately captured the pathological characteristics of these diseases, in both in vitro and in vivo settings. In addition, we transplanted the COs into NOD SCID mice and observed that they survived and exhibited ongoing expansion in vivo. Impressively, over a span of 75-day transplantation, these COs not only established blood vessel-like structures but also integrated with the host mice's vascular system. It is noteworthy that these COs developed to a size of approximately 8 mm in diameter, slightly surpassing the dimensions of the mouse heart. This innovative research highlighted the potential of our COs as a promising avenue for cardiovascular research and therapeutic exploration.

Heart-on-a-chip model of immune-induced cardiac dysfunction reveals the involvement of free mitochondrial DNA and therapeutic effects of endothelial exosomes (preprint)

Cardiovascular disease continues to take more human lives than all cancer combined, prompting the need for improved research models and treatment options. Despite a significant progress in development of mature heart-on-a-chip models of fibrosis and cardiomyopathies starting from induced pluripotent stem cells (iPSCs), human cell-based models of myocardial inflammation are lacking. Here, we bioengineered a vascularized heart-on-a-chip system with circulating immune cells to model SARS-CoV-2-induced acute myocarditis. Briefly, we observed hallmarks of COVID-19-induced myocardial inflammation in the heart-on-a-chip model, as the presence of immune cells augmented the expression levels of proinflammatory cytokines, triggered progressive impairment of contractile function and altered intracellular calcium transient activities. An elevation of circulating cell-free mitochondrial DNA (ccf-mtDNA) was measured first in the in vitro heart-on-a-chip model and then validated in COVID-19 patients with low left ventricular ejection fraction (LVEF), demonstrating that mitochondrial damage is an important pathophysiological hallmark of inflammation induced cardiac dysfunction. Leveraging this platform in the context of SARS-CoV-2 induced myocardial inflammation, we established that administration of human umbilical vein-derived EVs effectively rescued the contractile deficit, normalized intracellular calcium handling, elevated the contraction force and reduced the ccf- mtDNA and chemokine release via TLR-NF-kB signaling axis.

Single-cell RNA sequencing reveals characteristics of myeloid cells in pulmonary post-acute sequelae of SARS-CoV-2 (preprint)

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, the dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naive to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes and dendritic cells) was increased in PPASC compared to controls. MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naive samples. Conclusion: This study offers valuable insights into the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests their potential role as a driver of PPASC.

Expansion of profibrotic monocyte-derived alveolar macrophages in patients with persistent respiratory symptoms and radiographic abnormalities after COVID-19 (preprint)

As many as 10-30% of the over 760 million survivors of COVID-19 develop persistent symptoms, of which respiratory symptoms are among the most common. To understand the cellular and molecular basis for respiratory PASC, we combined a machine learning-based analysis of lung computed tomography (CT) with flow cytometry, single-cell RNA-sequencing analysis of bronchoalveolar lavage fluid and nasal curettage samples, and alveolar cytokine profiling in a cohort of thirty-five patients with respiratory symptoms and radiographic abnormalities more than 90 days after infection with COVID-19. CT images from patients with PASC revealed abnormalities involving 73% of the lung, which improved on subsequent imaging. Interstitial abnormalities suggestive of fibrosis on CT were associated with the increased numbers of neutrophils and presence of profibrotic monocyte-derived alveolar macrophages in BAL fluid, reflecting unresolved epithelial injury. Persistent infection with SARS-CoV-2 was identified in six patients and secondary bacterial or viral infections in two others. These findings suggest that despite its heterogenous clinical presentations, respiratory PASC with radiographic abnormalities results from a common pathobiology characterized by the ongoing recruitment of neutrophils and profibrotic monocyte-derived alveolar macrophages driving lung fibrosis with implications for diagnosis and therapy.

Nutritional Approaches in Children with Overweight or Obesity and Hepatic Steatosis.

Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities.

COVID-19-The Shift of Homeostasis into Oncopathology or Chronic Fibrosis in Terms of Female Reproductive System Involvement.

The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus remains a global public health concern due to the systemic nature of the infection and its long-term consequences, many of which remain to be elucidated. SARS-CoV-2 targets endothelial cells and blood vessels, altering the tissue microenvironment, its secretion, immune-cell subpopulations, the extracellular matrix, and the molecular composition and mechanical properties. The female reproductive system has high regenerative potential, but can accumulate damage, including due to SARS-CoV-2. COVID-19 is profibrotic and can change the tissue microenvironment toward an oncogenic niche. This makes COVID-19 and its consequences one of the potential regulators of a homeostasis shift toward oncopathology and fibrosis in the tissues of the female reproductive system. We are looking at SARS-CoV-2-induced changes at all levels in the female reproductive system.

Polygenic risk of idiopathic pulmonary fibrosis and COVID-19 severity (preprint)

Introduction. Coronavirus disease 2019 (COVID-19) survivors can develop residual lung abnormalities consistent with lung fibrosis. A shared genetic component between COVID-19 and idiopathic pulmonary fibrosis (IPF) has been shown. However, genetic overlap studies of IPF and COVID-19 have primarily concentrated on the IPF genome-wide significant risk variants that have been previously identified, rather than combined into a genome-wide polygenic risk. Here we used IPF genome-wide association study (GWAS) results to calculate polygenic risk scores (PRSs) and study their association with COVID-19 severity. Methods. We used results from the largest meta-GWAS of clinically defined IPF risk (base dataset; n=24,589) and individual-level imputed data from the SCOURGE study of patients with COVID-19 (target dataset; n=15,024). We calculated IPF PRSs using PRSice-2 and assessed their association with COVID-19 hospitalisation, severe illness, and critical illness. We also evaluated the effect of age and sex stratification. Results were validated using an independent PRS method. Enrichment analyses and pathway-specific PRSs were performed to study biological pathways associated with COVID-19 severity. Results. IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness. The strongest association was found in patients aged <60 years, especially among younger males (OR=1.16; 95%CI=1.08-1.25; p=6.39x10-5). A pathway enrichment analysis of the variants included in the best model fit and subsequent pathway-specific PRSs analyses supported the link of Cadherin and Integrin signalling pathways to COVID-19 severity when stratified by age and sex. Conclusion. Our results suggest that there is genome-wide genetic overlap between IPF and severe COVID-19 that is dependent on age and sex and adds further support that the pathogenesis of both IPF and severe COVID-19 share underlying biological mechanisms. This could imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.

The fatal trajectory of pulmonary COVID-19 is driven by lobular ischemia and fibrotic remodelling.

BACKGROUND: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9-20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. METHODS: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients' hospitalization time. FINDINGS: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. INTERPRETATION: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. FUNDING: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.

Identification of targets for drug repurposing to treat COVID-19 using a Deep Learning Neural Network (preprint)

The COVID-19 pandemic has resulted in a global public health crisis requiring immediate acute therapeutic solutions. To address this challenge, we developed a useful tool deep learning model using the graph-embedding convolution network (GECN) algorithm. Our approach identified COVID-19-related genes and potential druggable targets, including tyrosine kinase ABL1/2, pro-inflammatory cytokine CSF2, and pro-fibrotic cytokines IL-4 and IL-13. These target genes are implicated in critical processes related to COVID-19 pathogenesis, including endosomal membrane fusion, cytokine storm, and tissue fibrosis. Our analysis revealed that ABL kinase inhibitors, lenzilumab (anti-CSF2), and dupilumab (anti-IL4R) represent promising therapeutic solutions that can effectively block virus-host membrane fusion or attenuate hyperinflammation in COVID-19 patients. Compared to the traditional drug screening process, our GECN algorithm enables rapid analysis of disease-related human protein interaction networks and prediction of candidate drug targets from a large-scale knowledge graph in a cost-effective and efficient manner. Overall, Overall, our results suggest that the model has the potential to facilitate drug repurposing and aid in the fight against COVID-19.

Single cell meta-analysis of EndMT and EMT state in COVID-19.

COVID-19 prognoses suggests that a proportion of patients develop fibrosis, but there is no evidence to indicate whether patients have progression of mesenchymal transition (MT) in the lungs. The role of MT during the COVID-19 pandemic remains poorly understood. Using single-cell RNA sequencing, we profiled the transcriptomes of cells from the lungs of healthy individuals (n = 45), COVID-19 patients (n = 58), and idiopathic pulmonary fibrosis (IPF) patients (n = 64) human lungs to map the entire MT change. This analysis enabled us to map all high-resolution matrix-producing cells and identify distinct subpopulations of endothelial cells (ECs) and epithelial cells as the primary cellular sources of MT clusters during COVID-19. For the first time, we have identied early and late subgroups of endothelial mesenchymal transition (EndMT) and epithelial-mesenchymal transition (EMT) using analysis of public databases for single-cell sequencing. We assessed epithelial subgroups by age, smoking status, and gender, and the data suggest that the proportional changes in EMT in COVID-19 are statistically significant. Further enumeration of early and late EMT suggests a correlation between invasive genes and COVID-19. Finally, EndMT is upregulated in COVID-19 patients and enriched for more inflammatory cytokines. Further, by classifying EndMT as early or late stages, we found that early EndMT was positively correlated with entry factors but this was not true for late EndMT. Exploring the MT state of may help to mitigate the fibrosis impact of SARS-CoV-2 infection.

New therapeutic approaches against pulmonary fibrosis.

Pulmonary fibrosis is the end-stage change of a large class of lung diseases characterized by the proliferation of fibroblasts and the accumulation of a large amount of extracellular matrix, accompanied by inflammatory damage and tissue structure destruction, which also shows the normal alveolar tissue is damaged and then abnormally repaired resulting in structural abnormalities (scarring). Pulmonary fibrosis has a serious impact on the respiratory function of the human body, and the clinical manifestation is progressive dyspnea. The incidence of pulmonary fibrosis-related diseases is increasing year by year, and no curative drugs have appeared so far. Nevertheless, research on pulmonary fibrosis have also increased in recent years, but there are no breakthrough results. Pathological changes of pulmonary fibrosis appear in the lungs of patients with coronavirus disease 2019 (COVID-19) that have not yet ended, and whether to improve the condition of patients with COVID-19 by means of the anti-fibrosis therapy, which are the questions we need to address now. This review systematically sheds light on the current state of research on fibrosis from multiple perspectives, hoping to provide some references for design and optimization of subsequent drugs and the selection of anti-fibrosis treatment plans and strategies.

Comparison of two antifibrotic treatments for lung fibrosis in post-COVID-19 syndrome: A randomized, prospective study.

BACKGROUND: Although pulmonary fibrosis secondary to COVID-19 infection is uncommon, it can lead to problems if not treated effectively in the early period. This study aimed to compare the effects of treatment with nintedanib and pirfenidone in patients with COVID-19-related fibrosis. METHODS: Thirty patients who presented to the post-COVID outpatient clinic between May 2021 and April 2022 with a history of COVID-19 pneumonia and exhibited persistent cough, dyspnea, exertional dyspnea, and low oxygen saturation at least 12 weeks after diagnosis were included. The patients were randomized to receive off-label treatment with nintedanib or pirfenidone and were followed up for 12 weeks. RESULTS: After 12 weeks of treatment, all pulmonary function test (PFT) parameters, 6MWT distance, and oxygen saturation were increased compared to baseline in both the pirfenidone group and nintedanib groups, while heart rate and radiological score levels were decreased (p<0.05 for all). The changes in 6MWT distance and oxygen saturation were significantly greater in the nintedanib group than in the pirfenidone group (p=0.02 and 0.005, respectively). Adverse drug effects were more frequent with nintedanib than pirfenidone, with the most common being diarrhea, nausea, and vomiting. CONCLUSION: In patients with interstitial fibrosis after COVID-19 pneumonia, both nintedanib and pirfenidone were observed to be effective in improving radiological score and PFT parameters. Nintedanib was more effective than pirfenidone in increasing exercise capacity and saturation values but caused more adverse drug effects.

Lung transplantation for coronavirus disease 2019 acute respiratory distress syndrome/fibrosis: silver lining of a global pandemic.

PURPOSE OF REVIEW: The COVID-19 pandemic revolutionized the field of lung transplantation, as lung transplant is now an acceptable life-saving therapy for select patients with COVID-19-associated acute respiratory distress syndrome (ARDS), while prior to the pandemic, few transplants were performed for ARDS. This review article details the establishment of lung transplantation as a viable therapy for COVID-19-related respiratory failure, how to evaluate COVID-19 patients for lung transplant, and specific technical considerations for the operation. RECENT FINDINGS: Lung transplantation is a life-altering treatment for two distinct cohorts of COVID-19 patients: those with irrecoverable COVID-19-associated ARDS and those who recover from the initial COVID-19 insult but are left with chronic, debilitating post-COVID fibrosis. Both cohorts require stringent selection criteria and extensive evaluation to be listed for lung transplantation. As the first COVID-19 lung transplantation was recently performed, long-term outcomes are lacking; however, short-term outcome data of COVID-19-related lung transplants are promising. SUMMARY: Given the challenges and complexities associated with COVID-19-related lung transplantation, strict patient selection and evaluation are required with an experienced multidisciplinary team at a high-volume/resource center. With promising short-term outcome data, ongoing studies are needed to assess long-term outcomes of COVID-19-related lung transplants.

Pathology Outlines of Post-COVID-19 Pulmonary Fibrosis Comparative with Idiopathic Pulmonary Fibrosis (preprint)

This review brings together the current knowledge regarding the risk factors, and the clinical, radiologic and histological features of both post-COVID-19 interstitial pul-monary fibrosis (PCPF) and Idiopathic Pulmonary Fibrosis (IPF) with a particular fo-cus on describing the similarities and the disparities between the fibrotic changes in these two diseases. It is important to highlight the common points of PCPF and IPF to observe if they are some targetable changes to improve patient outcomes. The litera-ture review was performed using numerous databases to identify relevant articles published in English through October 2022. This review would help clinicians, pathologists and researchers to make an accurate diagnosis, which can be useful in identifying the group of patients who can be selected for antifibrotic therapies, and future therapeutic perspectives.

Fibrosis-4 index and mortality in coronavirus disease 2019: a meta-analysis.

BACKGROUND/AIMS: In this meta-analysis, we aimed to evaluate the prognostic value of fibrosis-4 index (FIB-4) in COVID-19. METHODS: We performed a comprehensive literature search of PubMed, Embase, and Scopus databases on 26 November 2020. FIB-4 was calculated by [age (years) × AST (IU/L)]/[platelet count (109/L) × âˆšALT (U/L)]. A value above cutoff point was considered high and a value below cutoff point was considered low. The main outcome was mortality, the association between high FIB-4 and mortality was reported in odds ratio (OR). Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic OR (DOR), area under the curve (AUC) were generated. RESULTS: There were 963 patients from five studies included in this systematic review and meta-analysis. Meta-analysis showed that high FIB-4 was associated with increased mortality [OR 3.96 (2.16-7.27), P < 0.001; I2: 41.3%]. High FIB-4 was associated mortality with a sensitivity of 0.56 (0.40-0.70), specificity of 0.80 (0.72-0.86), PLR 2.8 (1.8-4.2), NLR 0.55 (0.39-0.78), DOR 5 (2-10), and AUC of 0.77 (0.73-0.81). Fagan's nomogram indicated that for a pre-test probability (mortality) of 30%, a high FIB-4 was associated with 54% post-test probability and a low FIB-4 was associated with 19%, respectively. The funnel-plot analysis was asymmetrical, trim-and-fill analysis by imputation of a study on the left side using linear estimator resulted in an OR of 3.48 (1.97-6.14). Egger's test showed no indication of small-study effects (P = 0.881). CONCLUSION: High FIB-4 was associated with mortality in patients with COVID-19.

Inhibition of Myeloperoxidase Pro-Fibrotic Effect by Noscapine in Equine Endometrium.

Myeloperoxidase is an enzyme released by neutrophils when neutrophil extracellular traps (NETs) are formed. Besides myeloperoxidase activity against pathogens, it was also linked to many diseases, including inflammatory and fibrotic ones. Endometrosis is a fibrotic disease of the mare endometrium, with a large impact on their fertility, where myeloperoxidase was shown to induce fibrosis. Noscapine is an alkaloid with a low toxicity, that has been studied as an anti-cancer drug, and more recently as an anti-fibrotic molecule. This work aims to evaluate noscapine inhibition of collagen type 1 (COL1) induced by myeloperoxidase in equine endometrial explants from follicular and mid-luteal phases, at 24 and 48 h of treatment. The transcription of collagen type 1 alpha 2 chain (COL1A2), and COL1 protein relative abundance were evaluated by qPCR and Western blot, respectively. The treatment with myeloperoxidase increased COL1A2 mRNA transcription and COL1 protein, whereas noscapine was able to reduce this effect with respect to COL1A2 mRNA transcription, in a time/estrous cycle phase-dependent manner (in explants from the follicular phase, at 24 h of treatment). Our study indicates that noscapine is a promising drug to be considered as an anti-fibrotic molecule to prevent endometrosis development, making noscapine a strong candidate to be applied in future endometrosis therapies.

Modeling of Respiratory Diseases Evolving with Fibrosis from Organoids Derived from Human Pluripotent Stem Cells.

Respiratory disease is one of the leading causes of morbidity and mortality worldwide. There is no cure for most diseases, which are treated symptomatically. Hence, new strategies are required to deepen the understanding of the disease and development of therapeutic strategies. The advent of stem cell and organoid technology has enabled the development of human pluripotent stem cell lines and adequate differentiation protocols for developing both airways and lung organoids in different formats. These novel human-pluripotent-stem-cell-derived organoids have enabled relatively accurate disease modeling. Idiopathic pulmonary fibrosis is a fatal and debilitating disease that exhibits prototypical fibrotic features that may be, to some extent, extrapolated to other conditions. Thus, respiratory diseases such as cystic fibrosis, chronic obstructive pulmonary disease, or the one caused by SARS-CoV-2 may reflect some fibrotic aspects reminiscent of those present in idiopathic pulmonary fibrosis. Modeling of fibrosis of the airways and the lung is a real challenge due to the large number of epithelial cells involved and interaction with other cell types of mesenchymal origin. This review will focus on the status of respiratory disease modeling from human-pluripotent-stem-cell-derived organoids, which are being used to model several representative respiratory diseases, such as idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease, and COVID-19.