scholarly journals R-SPONDIN2+ Mesenchymal Cells Form the Bud Tip Progenitor Niche During Human Lung Development

2021 ◽  
Author(s):  
Renee F.C. Hein ◽  
Joshua H. Wu ◽  
Yu-Hwai Tsai ◽  
Angeline Wu ◽  
Alyssa J. Miller ◽  
...  
Keyword(s):  
Lung Development ◽  
Human Lung ◽  
System Development ◽  
Mesenchymal Cell ◽  
Mesenchymal Cells ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing ◽  
Explant Cultures ◽  
Lung Progenitors ◽  
And Function

SUMMARYMammalian respiratory system development is regulated by complex reciprocal signaling events that take place between epithelial cells and the surrounding mesenchymal cells; however, mesenchymal heterogeneity and function in the developing human lung is poorly understood. We interrogated single cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist R-SPONDIN2 (RSPO2), and we found that adjacent epithelial bud tip progenitors are enriched for the RSPO2 receptor LGR5. By carrying out functional experiments using organoid models, lung explant cultures, and FACS-isolated RSPO2+ mesenchyme, we show that RSPO2 is a critical niche cue that potentiates WNT signaling in human lung progenitors to maintain their multipotency.

scholarly journals Use of three-dimensional organoids and lung-on-a-chip methods to study lung development, regeneration and disease

2018 ◽  
Vol 52 (5) ◽  
pp. 1800876 ◽  
Author(s):  
Konstantinos Gkatzis ◽  
Sara Taghizadeh ◽  
Dongeun Huh ◽  
Didier Y.R. Stainier ◽  
Saverio Bellusci
Keyword(s):  
Pluripotent Stem Cells ◽  
Lung Development ◽  
Animal Studies ◽  
Human Lung ◽  
Unmet Need ◽  
Three Dimensional ◽  
Lung Cells ◽  
Lung Physiology ◽  
And Function

Differences in lung anatomy between mice and humans, as well as frequently disappointing results when using animal models for drug discovery, emphasise the unmet need for in vitro models that can complement animal studies and improve our understanding of human lung physiology, regeneration and disease. Recent papers have highlighted the use of three-dimensional organoids and organs-on-a-chip to mimic tissue morphogenesis and function in vitro. Here, we focus on the respiratory system and provide an overview of these in vitro models, which can be derived from primary lung cells and pluripotent stem cells, as well as healthy or diseased lungs. We emphasise their potential application in studies of respiratory development, regeneration and disease modelling.

scholarly journals Glycogen Synthase Kinase 3 induces multilineage maturation of human pluripotent stem cell-derived lung progenitors in 3D culture

2018 ◽  
Author(s):  
Ana Luisa Rodrigues Toste de Carvalho ◽  
Alexandros Strikoudis ◽  
Tiago J. Dantas ◽  
Ya-Wen Chen ◽  
Hsiao-Yun Liu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Lung Development ◽  
Human Lung ◽  
Glycogen Synthase ◽  
3D Culture ◽  
Alveolar Epithelial Cells ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Type I ◽  
Lung Progenitors

Although strategies for directed differentiation of human pluripotent stem cells (hPSCs) into lung and airway have been established, terminal maturation of the cells remains a vexing problem. We show here that in Collagen I 3D cultures in the absence of glycogen synthase kinase 3 (GSK3) inhibition, hPSC-derived lung progenitors (LPs) undergo multilineage maturation into proximal cells arranged in pseudostratified epithelia, type I alveolar epithelial cells and morphologically mature type II cells. Enhanced cell cycling, one of the signaling outputs of GSK3 inhibition, plays a role in the maturation-inhibiting effect of GSK3 inhibition. Using this model, we show NOTCH signaling induced a distal at the expense of a proximal and ciliated cell fate, while WNT signaling promoted a proximal, club cell fate, thus implicating both signaling pathways in proximodistal specification in human lung development. These findings establish an approach to achieve multilineage maturation of lung and airway cells from hPSCs, demonstrate a pivotal role of GSK3 in the maturation of lung progenitors, and provide novel insight into proximodistal specification during human lung development.

scholarly journals Background Contamination Correction in Human Lung Single-Cell RNA Sequencing Data

2020 ◽  
Author(s):  
W. Zang ◽  
J.C. Schupp ◽  
M.J. Kane ◽  
T.S. Adams ◽  
S. Poli De Frias ◽  
...  
Keyword(s):  
Single Cell ◽  
Rna Sequencing ◽  
Human Lung ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing

scholarly journals In Vitro Models to Study Human Lung Development, Disease and Homeostasis

Physiology ◽  
2017 ◽  
Vol 32 (3) ◽  
pp. 246-260 ◽  
Author(s):  
Alyssa J. Miller ◽  
Jason R. Spence
Keyword(s):  
Animal Models ◽  
Lung Development ◽  
Human Lung ◽  
In Vitro Models ◽  
Structure And Function ◽  
Tissue Cell ◽  
Main Function ◽  
Human Pluripotent Stem Cell ◽  
And Function

The main function of the lung is to support gas exchange, and defects in lung development or diseases affecting the structure and function of the lung can have fatal consequences. Most of what we currently understand about human lung development and disease has come from animal models. However, animal models are not always fully able to recapitulate human lung development and disease, highlighting an area where in vitro models of the human lung can compliment animal models to further understanding of critical developmental and pathological mechanisms. This review will discuss current advances in generating in vitro human lung models using primary human tissue, cell lines, and human pluripotent stem cell derived lung tissue, and will discuss crucial next steps in the field.

scholarly journals A Single Cell Atlas of Lung Development

2021 ◽  
Author(s):  
Nicholas M. Negretti ◽  
Erin J. Plosa ◽  
John T. Benjamin ◽  
Bryce A. Schuler ◽  
A. Christian Habermann ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Development ◽  
Spatial Organization ◽  
Single Cell Rna Sequencing ◽  
And Function ◽  
Parenchymal Cells ◽  
Computational Analyses ◽  
Spatiotemporal Localization

SummaryLung organogenesis requires precisely timed shifts in the spatial organization and function of parenchymal cells, especially during the later stages of lung development. To investigate the mechanisms governing lung parenchymal dynamics during development, we performed a single cell RNA sequencing (scRNA-seq) time-series yielding 92,238 epithelial, endothelial, and mesenchymal cells across 8 time points from embryonic day 12 (E12) to postnatal day 14 (P14) in mice. We combined new computational analyses with RNA in situ hybridization to explore transcriptional velocity, fate likelihood prediction, and spatiotemporal localization of cell populations during the transition between the saccular and alveolar stages. We interrogated this atlas to illustrate the complexity of type 1 pneumocyte function during the saccular and alveolar stages, and we demonstrate an integrated view of the cellular dynamics during lung development.

scholarly journals IMMU-27. SINGLE CELL RNA-SEQUENCING IDENTIFIES NOVEL BONE MARROW DERIVED MYELOID CELLS IN GLIOBLASTOMA ASSOCIATED WITH TUMOR AGGRESSION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii110-ii110
Author(s):  
Christina Jackson ◽  
Christopher Cherry ◽  
Sadhana Bom ◽  
Hao Zhang ◽  
John Choi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Cell ◽  
Tumor Cells ◽  
Rna Sequencing ◽  
Metabolic Pathways ◽  
Myeloid Cells ◽  
Tumor Grade ◽  
Sequencing Data ◽  
Single Cell Rna Sequencing ◽  
Two Populations

Abstract BACKGROUND Glioma associated myeloid cells (GAMs) can be induced to adopt an immunosuppressive phenotype that can lead to inhibition of anti-tumor responses in glioblastoma (GBM). Understanding the composition and phenotypes of GAMs is essential to modulating the myeloid compartment as a therapeutic adjunct to improve anti-tumor immune response. METHODS We performed single-cell RNA-sequencing (sc-RNAseq) of 435,400 myeloid and tumor cells to identify transcriptomic and phenotypic differences in GAMs across glioma grades. We further correlated the heterogeneity of the GAM landscape with tumor cell transcriptomics to investigate interactions between GAMs and tumor cells. RESULTS sc-RNAseq revealed a diverse landscape of myeloid-lineage cells in gliomas with an increase in preponderance of bone marrow derived myeloid cells (BMDMs) with increasing tumor grade. We identified two populations of BMDMs unique to GBMs; Mac-1and Mac-2. Mac-1 demonstrates upregulation of immature myeloid gene signature and altered metabolic pathways. Mac-2 is characterized by expression of scavenger receptor MARCO. Pseudotime and RNA velocity analysis revealed the ability of Mac-1 to transition and differentiate to Mac-2 and other GAM subtypes. We further found that the presence of these two populations of BMDMs are associated with the presence of tumor cells with stem cell and mesenchymal features. Bulk RNA-sequencing data demonstrates that gene signatures of these populations are associated with worse survival in GBM. CONCLUSION We used sc-RNAseq to identify a novel population of immature BMDMs that is associated with higher glioma grades. This population exhibited altered metabolic pathways and stem-like potentials to differentiate into other GAM populations including GAMs with upregulation of immunosuppressive pathways. Our results elucidate unique interactions between BMDMs and GBM tumor cells that potentially drives GBM progression and the more aggressive mesenchymal subtype. Our discovery of these novel BMDMs have implications in new therapeutic targets in improving the efficacy of immune-based therapies in GBM.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

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