scholarly journals Acquisition of alveolar fate and differentiation competence by human fetal lung epithelial progenitor cells

2021 ◽  
Author(s):  
Kyungtae Lim ◽  
Walfred Tang ◽  
Dawei Sun ◽  
Peng He ◽  
Sarah Teichmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Human Lung ◽  
Fetal Lung ◽  
Alveolar Type ◽  
Alveolar Development ◽  
Wnt Inhibitor ◽  
Key Aspects ◽  
Epithelial Progenitor Cells

Variation in lung alveolar development is strongly linked to disease susceptibility. However, the cellular and molecular mechanisms underlying alveolar development are difficult to study in humans. Using primary human fetal lungs we have characterized a tip progenitor cell population with alveolar fate potential. These data allowed us to benchmark a self-organising organoid system which captures key aspects of lung lineage commitment and can be efficiently differentiated to alveolar type 2 cell fate. Our data show that Wnt and FGF signalling, and the downstream transcription factors NKX2.1 and TFAP2C, promote human alveolar or airway fate respectively. Moreover, we have functionally validated cell-cell interactions in human lung alveolar patterning. We show that Wnt signalling from differentiating fibroblasts promotes alveolar type 2 cell identity, whereas myofibroblasts secrete the Wnt inhibitor, NOTUM, providing spatial patterning. Our organoid system recapitulates key aspects of human lung development allowing mechanistic experiments to determine the underpinning molecular regulation.

scholarly journals Insulin resistance and cancer: the role of insulin and IGFs

2012 ◽  
Vol 20 (1) ◽  
pp. R1-R17 ◽  
Author(s):  
Sefirin Djiogue ◽  
Armel Hervé Nwabo Kamdje ◽  
Lorella Vecchio ◽  
Maulilio John Kipanyula ◽  
Mohammed Farahna ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Proliferation ◽  
Energy Metabolism ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Epidemiological Studies ◽  
High Energy

Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

scholarly journals Stretch increases alveolar type 1 cell number in fetal lungs through ROCK-Yap/Taz pathway

2021 ◽  
Author(s):  
Tram Mai Nguyen ◽  
Johannes van der Merwe ◽  
Linda Elowsson Rendin ◽  
Anna-Karin Larsson-Callerfelt ◽  
Jan Deprest ◽  
...  
Keyword(s):  
Lung Development ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Fluid Pressure ◽  
Fetal Lung ◽  
In Vivo Model ◽  
Alveolar Type ◽  
Ex Vivo Model

Accurate fluid pressure in the fetal lung is critical for its development, especially at the beginning of the saccular stage when alveolar epithelial type 1 (AT1) and type 2 (AT2) cells differentiate from the epithelial progenitors. Despite our growing understanding of the role of physical forces in lung development, the molecular mechanisms that regulate the transduction of mechanical stretch to alveolar differentiation remain elusive. To simulate lung distension, we optimized both an ex vivo model with precision cut lung slices and an in vivo model of fetal tracheal occlusion. Increased mechanical tension showed to improve alveolar maturation and differentiation towards AT1. By manipulating ROCK pathway, we demonstrate that stretch-induced Yap/Taz activation promotes alveolar differentiation towards AT1 phenotype via ROCK activity. Our findings show that balanced ROCK-Yap/Taz signaling is essential to regulate AT1 differentiation in response to mechanical stretching of the fetal lung, which might be helpful in improving lung development and regeneration.

scholarly journals Microstructured hydrogels to guide self-assembly and function of lung alveolospheres

2021 ◽  
Author(s):  
Claudia Loebel ◽  
Aaron I. Weiner ◽  
Jeremy B. Katzen ◽  
Michael P. Morley ◽  
Vikram Bala ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
3D Culture ◽  
Size Composition ◽  
Mouse Tissue ◽  
Alveolar Type ◽  
Primary Mouse ◽  
Defined Culture

AbstractEpithelial cell organoids have increased opportunities to probe questions on tissue development and disease in vitro and for therapeutic cell transplantation. Despite their potential, current protocols to grow these organoids almost exclusively depend on culture within three-dimensional (3D) Matrigel, which limits defined culture conditions, introduces animal components, and results in heterogenous organoids (i.e., shape, size, composition). Here, we describe a method that relies on polymeric hydrogel substrates for the generation and expansion of lung alveolar organoids (alveolospheres). Using synthetic hydrogels with defined chemical and physical properties, human induced pluripotent stem cell (iPSC)-derived alveolar type 2 cells (iAT2s) self-assemble into alveolospheres and propagate in Matrigel-free conditions. By engineering pre-defined microcavities within these hydrogels, the heterogeneity of alveolosphere size and structure was reduced when compared to 3D culture while maintaining alveolar type 2 cell fate of human iAT2 and primary mouse tissue-derived progenitor cells. This hydrogel system is a facile and accessible culture system for the culture of primary and iPSC-derived lung progenitors and the method could be expanded to the culture of other epithelial progenitor and stem cell aggregates.

scholarly journals SARS-CoV-2 Infection of Pluripotent Stem Cell-Derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

2020 ◽  
Vol 27 (6) ◽  
pp. 962-973.e7 ◽  
Author(s):  
Jessie Huang ◽  
Adam J. Hume ◽  
Kristine M. Abo ◽  
Rhiannon B. Werder ◽  
Carlos Villacorta-Martin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Inflammatory Response ◽  
Pluripotent Stem Cell ◽  
Human Lung ◽  
Alveolar Type

scholarly journals The aging transcriptome and cellular landscape of the human lung in relation to SARS-CoV-2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ryan D. Chow ◽  
Medha Majety ◽  
Sidi Chen
Keyword(s):  
Stress Responses ◽  
Human Lung ◽  
Airway Smooth Muscle Cells ◽  
Alveolar Type ◽  
Basal Cells ◽  
Deconvolution Analysis ◽  
Cellular Replication ◽  
Older Populations

AbstractAge is a major risk factor for severe coronavirus disease-2019 (COVID-19). Here, we interrogate the transcriptional features and cellular landscape of the aging human lung. By intersecting these age-associated changes with experimental data on SARS-CoV-2, we identify several factors that may contribute to the heightened severity of COVID-19 in older populations. The aging lung is transcriptionally characterized by increased cell adhesion and stress responses, with reduced mitochondria and cellular replication. Deconvolution analysis reveals that the proportions of alveolar type 2 cells, proliferating basal cells, goblet cells, and proliferating natural killer/T cells decrease with age, whereas alveolar fibroblasts, pericytes, airway smooth muscle cells, endothelial cells and IGSF21+ dendritic cells increase with age. Several age-associated genes directly interact with the SARS-CoV-2 proteome. Age-associated genes are also dysregulated by SARS-CoV-2 infection in vitro and in patients with severe COVID-19. These analyses illuminate avenues for further studies on the relationship between age and COVID-19.

scholarly journals SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

2020 ◽  
Author(s):  
Jessie Huang ◽  
Adam J. Hume ◽  
Kristine M. Abo ◽  
Rhiannon B. Werder ◽  
Carlos Villacorta-Martin ◽  
...  
Keyword(s):  
Target Genes ◽  
Human Lung ◽  
Human Model ◽  
Alveolar Type ◽  
Alveolar Cells ◽  
Protease Inhibition ◽  
Alveolar Epithelial ◽  
Distal Lung

ABSTRACTThe most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present an in vitro human model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death of these key alveolar facultative progenitors, as is observed in vivo in COVID-19 lung autopsies. Importantly, drug testing using iAT2s confirmed an antiviral dose-response to remdesivir and demonstrated the efficacy of TMPRSS2 protease inhibition, validating a putative mechanism used for viral entry in human alveolar cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection, providing a physiologically relevant platform for further drug development and facilitating a deeper understanding of COVID-19 pathogenesis.

scholarly journals Dnmt1 is required for proximal-distal patterning of the lung endoderm and for restraining alveolar type 2 cell fate

2019 ◽  
Vol 454 (2) ◽  
pp. 108-117 ◽  
Author(s):  
Derek C. Liberti ◽  
Jarod A. Zepp ◽  
Christina A. Bartoni ◽  
Kyle H. Liberti ◽  
Su Zhou ◽  
...  
Keyword(s):  
Cell Fate ◽  
Alveolar Type

scholarly journals Cryobanking of human distal lung epithelial cells for preservation of their phenotypic and functional characteristics.

2021 ◽  
Author(s):  
Bindu Konda ◽  
Apoorva Mulay ◽  
Changfu Yao ◽  
Edo Israely ◽  
Stephen Beil ◽  
...  
Keyword(s):  
Single Cell ◽  
Lung Tissue ◽  
Human Lung ◽  
Alveolar Type ◽  
Basal Cells ◽  
Human Lung Tissue ◽  
Downstream Analysis ◽  
Long Term Preservation

The epithelium lining airspaces of the human lung is maintained by regional stem cells including basal cells of pseudostratified airways and alveolar type 2 pneumocytes (AT2) of the alveolar gas-exchange region. Despite effective methods for long-term preservation of airway basal cells, methods for efficient preservation of functional epithelial cell types of the distal gas-exchange region are lacking. Here we detail a method for cryobanking of epithelial cells from either mouse or human lung tissue for preservation of their phenotypic and functional characteristics. Flow cytometric profiling, epithelial organoid-forming efficiency, and single cell transcriptomic analysis, were used to compare cells recovered from cryopreserved tissue with those of freshly dissociated tissue. Alveolar type 2 cells within single cell suspensions of enzymatically digested cryobanked distal lung tissue retained expression of the pan-epithelial marker CD326 and the AT2 cell surface antigen recognized by monoclonal antibody HTII-280, allowing antibody-mediated enrichment and downstream analysis. Isolated AT2 cells from cryobanked tissue were comparable with those of freshly dissociated tissue both in their single cell transcriptome and their capacity for in vitro organoid formation in 3D cultures. We conclude that the cryobanking method described herein allows long-term preservation of distal human lung tissue for downstream analysis of lung cell function and molecular phenotype, and is ideally suited for creation of an easily accessible tissue resource for the research community.

scholarly journals Differentiation of mouse fetal lung alveolar progenitors in serum-free organotypic cultures

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Konstantinos Gkatzis ◽  
Paolo Panza ◽  
Sofia Peruzzo ◽  
Didier YR Stainier
Keyword(s):  
Cell Fate ◽  
Fetal Lung ◽  
Casein Kinase ◽  
Alveolar Type ◽  
Alveolar Cells ◽  
Lung Maturation ◽  
Serum Free ◽  
Lung Epithelial ◽  
Distal Lung

Lung epithelial progenitors differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells. These cells form the air-blood interface and secrete surfactant, respectively, and are essential for lung maturation and function. Current protocols to derive and culture alveolar cells do not faithfully recapitulate the architecture of the distal lung, which influences cell fate patterns in vivo. Here, we report serum-free conditions that allow for growth and differentiation of mouse distal lung epithelial progenitors. We find that Collagen I promotes the differentiation of flattened, polarized AT1 cells. Using these organoids, we performed a chemical screen to investigate WNT signaling in epithelial differentiation. We identify an association between Casein Kinase activity and maintenance of an AT2 expression signature; Casein Kinase inhibition leads to an increase in AT1/progenitor cell ratio. These organoids provide a simplified model of alveolar differentiation and constitute a scalable screening platform to identify and analyze cell differentiation mechanisms.

scholarly journals Release of Notch activity coordinated by IL-1β signalling confers differentiation plasticity of airway progenitors via Fosl2 during alveolar regeneration

2021 ◽  
Author(s):  
Jinwook Choi ◽  
Yu Jin Jang ◽  
Catherine Dabrowska ◽  
Elhadi Iich ◽  
Kelly Evans ◽  
...  
Keyword(s):  
Cell Fate ◽  
Adult Stem Cells ◽  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Secretory Cells ◽  
Alveolar Type ◽  
Fate Decision ◽  
Cell Fate Conversion ◽  
Epigenetic Signatures

While the acquisition of cellular plasticity in adult stem cells is essential for rapid regeneration after tissue injury, little is known about the underlying molecular mechanisms governing this process. Our data reveal the coordination of airway progenitor differentiation plasticity by inflammatory signals during alveolar regeneration. Upon damage, IL-1β signalling-dependent modulation of Jag1/2 expression in ciliated cells results in the inhibition of Notch signalling in secretory cells, which drives reprogramming and acquisition of differentiation plasticity. We identify a core role for the transcription factor Fosl2/Fra2 in secretory cell fate conversion to alveolar type 2 (AT2) cells retaining the distinct genetic and epigenetic signatures of secretory lineages. We furthermore reveal that KDR/FLK-1+ human secretory cells display a conserved capacity to generate AT2 cells via Notch inhibition. Our results demonstrate the functional role of a IL-1β-Notch-Fosl2 axis for the fate decision of secretory cells during injury repair, proposing a new potential therapeutic target for human lung alveolar regeneration.

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