scholarly journals Comprehensive anatomic ontologies for lung development: A comparison of alveolar formation and maturation within mouse and human lung

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Huaqin Pan ◽  
◽  
Gail H. Deutsch ◽  
Susan E. Wert ◽  
Keyword(s):  
Lung Development ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Development Program ◽  
Comparative Approach ◽  
Data Annotation ◽  
Blood Institute ◽  
Human Lungs ◽  
Architectural Organization ◽  
Alveolar Formation

Abstract Background Although the mouse is widely used to model human lung development, function, and disease, our understanding of the molecular mechanisms involved in alveolarization of the peripheral lung is incomplete. Recently, the Molecular Atlas of Lung Development Program (LungMAP) was funded by the National Heart, Lung, and Blood Institute to develop an integrated open access database (known as BREATH) to characterize the molecular and cellular anatomy of the developing lung. To support this effort, we designed detailed anatomic and cellular ontologies describing alveolar formation and maturation in both mouse and human lung. Description While the general anatomic organization of the lung is similar for these two species, there are significant variations in the lung’s architectural organization, distribution of connective tissue, and cellular composition along the respiratory tract. Anatomic ontologies for both species were constructed as partonomic hierarchies and organized along the lung’s proximal-distal axis into respiratory, vascular, neural, and immunologic components. Terms for developmental and adult lung structures, tissues, and cells were included, providing comprehensive ontologies for application at varying levels of resolution. Using established scientific resources, multiple rounds of comparison were performed to identify common, analogous, and unique terms that describe the lungs of these two species. Existing biological and biomedical ontologies were examined and cross-referenced to facilitate integration at a later time, while additional terms were drawn from the scientific literature as needed. This comparative approach eliminated redundancy and inconsistent terminology, enabling us to differentiate true anatomic variations between mouse and human lungs. As a result, approximately 300 terms for fetal and postnatal lung structures, tissues, and cells were identified for each species. Conclusion These ontologies standardize and expand current terminology for fetal and adult lungs, providing a qualitative framework for data annotation, retrieval, and integration across a wide variety of datasets in the BREATH database. To our knowledge, these are the first ontologies designed to include terminology specific for developmental structures in the lung, as well as to compare common anatomic features and variations between mouse and human lungs. These ontologies provide a unique resource for the LungMAP, as well as for the broader scientific community.

scholarly journals Single cell transcriptomic profiling identifies molecular phenotypes of newborn human lung cells

2020 ◽  
Author(s):  
Soumyaroop Bhattacharya ◽  
Jacquelyn L. Myers ◽  
Cameron Baker ◽  
Minzhe Guo ◽  
Soula Danopoulos ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Development ◽  
Human Lung ◽  
Development Program ◽  
Molecular Profile ◽  
Mouse Lung ◽  
Lung Cells ◽  
Analysis Tool ◽  
Human Lung Cells ◽  
Human And Mouse

AbstractWhile animal model studies have extensively defined mechanisms controlling cell diversity in the developing mammalian lung, the limited data available from late stage human lung development represents a significant knowledge gap. The NHLBI Molecular Atlas of Lung Development Program (LungMAP) seeks to fill this gap by creating a structural, cellular and molecular atlas of the human and mouse lung. Single cell RNA sequencing generated transcriptional profiles of 5500 cells obtained from two newborn human lungs from the LungMAP Human Tissue Core Biorepository. Frozen single cell isolates were captured, and library preparation was completed on the Chromium 10X system. Data was analyzed in Seurat, and cellular annotation was performed using the ToppGene functional analysis tool. Single cell sequence data from an additional 32000 postnatal day 1 through 10 mouse lung cells generated by the LungMAP Cincinnati Research Center was integrated with the human data. Transcriptional interrogation of newborn human lung cells identified distinct clusters representing multiple populations of epithelial, endothelial, fibroblasts, pericytes, smooth muscle, and immune cells and signature genes for each of these population. Computational integration of newborn human and postnatal mouse lung development cellular transcriptomes facilitated the identification of distinct epithelial lineages including AT1, AT2 and ciliated epithelial cells. Integration of the newborn human and mouse cellular transcriptomes also demonstrated cell type-specific differences in maturation states of newborn human lung cells. In particular, newborn human lung matrix fibroblasts could be separated into those representative of younger cells (n=393), or older cells (n=158). Cells with each molecular profile were spatially resolved within newborn human lung tissue. This is the first comprehensive molecular map of the cellular landscape of neonatal human lung, including biomarkers for cells at distinct states of maturity.

scholarly journals A single-cell atlas of human fetal lung development between 14 and 19 weeks of gestation

2021 ◽  
Author(s):  
Laurent Renesme ◽  
Flore Lesage ◽  
David Cook ◽  
Shumei Zhong ◽  
Satu M Hanninen ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Development ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Cell Communication ◽  
Cell Types ◽  
Developmental Trajectory ◽  
Marker Genes ◽  
Different Cell Types ◽  
Pseudoglandular Stage

Rationale: Human lung development has been mainly described in morphologic studies and the potential underlying molecular mechanisms were extrapolated from animal models. Therefore, there is a need to gather knowledge from native human lung tissue. In this study we describe changes at a single-cell level in human fetal lungs during the pseudoglandular stage. Methods: We report the cellular composition, cell trajectories and cell-to-cell communication in developing human lungs with single-nuclei RNA sequencing (snRNA-seq) on 23,251 nuclei isolated from nine human fetuses with gestational ages between 14 to 19 weeks of gestation. Results: We identified nine different cell types, including a rare pulmonary neuroendocrine cells population. For each cell type, marker genes are reported, and selected marker genes are used for spatial validation with fluorescent RNA in situ hybridization. Enrichment and developmental trajectory analysis provide insight into molecular mechanisms and signaling pathways within individual cell clusters according to gestational age. Lastly, ligand-receptor analysis highlights determinants of cell-to-cell communication among the different cell types through the pseudoglandular stage, including general developmental pathways (NOTCH and TGFB), as well as more specific pathways involved in vasculogenesis, neurogenesis, and immune system regulation. Conclusion: These findings provide a clinically relevant background for research hypotheses generation in projects studying normal or impaired lung development and help to develop and validate surrogate models to study human lung development, such as human lung organoids.

scholarly journals PRMT5 Promotes EMT Through Regulating Akt Activity in Human Lung Cancer

2021 ◽  
Vol 30 ◽  
pp. 096368972110017
Author(s):  
Jianhao Huang ◽  
Yonghua Zheng ◽  
Xiao Zheng ◽  
Bao Qian ◽  
Qi Yin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Akt Signaling ◽  
Lung Cancer Cells ◽  
Signaling Cascades ◽  
Human Lung Cancer ◽  
Mesenchymal Transition ◽  
Human Lung Cancer Cells

The type II protein arginine methyltransferase 5 (PRMT5) has been engaged in various human cancer development and progression types. Nevertheless, few studies uncover the biological functions of PRMT5 in the epithelial-mesenchymal transition (EMT) of human lung cancer cells, and the associated molecular mechanisms and signaling cascades are entirely unknown. Here, we show that PRMT5 is the ectopic expression in human lung cancer tissues and cell lines. Further study reveals that silencing PRMT5 by lentivirus-mediated shRNA or blocking of PRMT5 by specific inhibitor GSK591 attenuates the expression levels of EMT-related markers in vivo, using the xenograft mouse model. Moreover, our results show that down-regulation of PRMT5 impairs EGFR/Akt signaling cascades in human lung cancer cells, whereas re-expression of PRMT5 recovers those changes, suggesting that PRMT5 regulates EMT probably through EGFR/Akt signaling axis. Altogether, our results demonstrate that PRMT5 serves as a critical oncogenic regulator and promotes EMT in human lung cancer cells. More importantly, our findings also suggest that PRMT5 may be a potential therapeutic candidate for the treatment of human lung cancer.

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development

2005 ◽  
Vol 94 (07) ◽  
pp. 175-183 ◽  
Author(s):  
Julie Ryu ◽  
Alfin G. Vicencio ◽  
Michael E. Yeager ◽  
Michael Kashgarian ◽  
Gabriel G. Haddad ◽  
...  
Keyword(s):  
Growth Factor ◽  
Lung Development ◽  
Epithelial To Mesenchymal Transition ◽  
Developmental Stages ◽  
Human Lung ◽  
Matrix Metalloproteases ◽  
Mouse Lung ◽  
Mesenchymal Transition ◽  
Expression Arrays ◽  
Human And Mouse

SummaryLung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increasedTIMP-3 expression. MMP-14, MMP-20,TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O2), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2.These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

2020 ◽  
Author(s):  
Hin Chu ◽  
Bingjie Hu ◽  
Xiner Huang ◽  
Yue Chai ◽  
Yixin Wang ◽  
...  
Keyword(s):  
Human Lung ◽  
Ex Vivo ◽  
Sialic Acids ◽  
Lung Epithelial Cells ◽  
Human Lung Tissue ◽  
Human Lungs ◽  
Lung Epithelial ◽  
Viral Determinants ◽  
Attachment Factor ◽  
Human Lung Epithelial Cells

Abstract SARS-CoV-2 has affected over 9 million patients with more than 460,000 deaths in about 6 months. Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells, which are not previously reported, may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we reported key host and viral determinants that were essential for efficient SARS-CoV-2 infection in the human lung. First, we identified heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Second, we demonstrated that while cell surface sialic acids significantly restricted SARS-CoV infection, SARS-CoV-2 could largely overcome sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissue explants. Third, we demonstrated that the inserted furin-like cleavage site in SARS-CoV-2 spike was required for efficient virus replication in human lung but not intestine tissues. Overall, these findings contributed to our understanding on efficient SARS-CoV-2 infection of human lungs.

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