Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated. DOI: http://dx.doi.org/10.7554/eLife.26575.001

• Publication year

  2017

• Venue

  eLife

• Publication date

  2017-06-30

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7554/eLife.26575PMID 28665271PMCID 5555721
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Explorer A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo

  2016cited by this paper
• Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung.

  2016cited by this paper
• Age, Sexual Dimorphism, and Disease Associations in the Developing Human Fetal Lung Transcriptome.

  2016cited by this paper
• Lung epithelial tip progenitors integrate glucocorticoid- and STAT3-mediated signals to control progeny fate

  2016influential reference
• Replication of human noroviruses in stem cell–derived human enteroids

  2016cited by this paper
• How to Grow a Lung: Applying Principles of Developmental Biology to Generate Lung Lineages from Human Pluripotent Stem Cells

  2016cited by this paper
• Insm1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes1.

  2015cited by this paper
• Insm 1 controls the differentiation of pulmonary neuroendocrine cells by repressing Hes 1

  2015cited by this paper
• Lung endoderm morphogenesis: gasping for form and function.

  2015cited by this paper
• Evidence for the involvement of fibroblast growth factor 10 in lipofibroblast formation during embryonic lung development

  2015cited by this paper
• Efficient genetic engineering of human intestinal organoids using electroporation

  2015influential reference
• CALL FOR PAPERS Bioengineering the Lung: Molecules, Materials, Matrix, Morphology, and Mechanics Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung

  2015cited by this paper
• Long-Term Culture of Genome-Stable Bipotent Stem Cells from Adult Human Liver

  2015cited by this paper
• Modeling mouse and human development using organoid cultures

  2015cited by this paper
• Expression of Carcinoembryonic Cell Adhesion Molecule 6 and Alveolar Epithelial Cell Markers in Lungs of Human Infants with Chronic Lung Disease

  2015cited by this paper
• Hox5 Genes Regulate the Wnt2/2b-Bmp4-Signaling Axis during Lung Development.

  2015cited by this paper
• Plasticity of Hopx+ Type I alveolar cells to regenerate Type II cells in the lung

  2015cited by this paper
• Wnt and FGF mediated epithelial‐mesenchymal crosstalk during lung development

  2015cited by this paper
• Efficient genetic engineering of human intestinal organoids using electroporation

  2015cited by this paper
• The miR-200 Family and Its Targets Regulate Type II Cell Differentiation in Human Fetal Lung*

  2015cited by this paper
• Reconstructing lineage hierarchies of the distal lung epithelium using single cell RNA-seq

  2014cited by this paper
• Two Nested Developmental Waves Demarcate a Compartment Boundary in the Mouse Lung

  2014cited by this paper
• The hippo pathway effector Yap controls patterning and differentiation of airway epithelial progenitors.

  2014cited by this paper
• Gene Expression Profiling in Human Lung Development: An Abundant Resource for Lung Adenocarcinoma Prognosis

  2014cited by this paper
• Alveolar progenitor and stem cells in lung development, renewal and cancer

  2014cited by this paper
• Hmga2 is required for canonical WNT signaling during lung development

  2014cited by this paper
• Normalization of RNA-seq data using factor analysis of control genes or samples

  2014cited by this paper
• Lung epithelial branching program antagonizes alveolar differentiation

  2013cited by this paper
• A functional CFTR assay using primary cystic fibrosis intestinal organoids

  2013cited by this paper
• Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

  2013cited by this paper
• Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors

  2013cited by this paper
• Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis

  2013cited by this paper
• Modeling human disease with pluripotent stem cells: from genome association to function.

  2013cited by this paper
• In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration

  2013cited by this paper
• Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny

  2013cited by this paper
• Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.

  2013cited by this paper
• Type 2 alveolar cells are stem cells in adult lung.

  2013cited by this paper
• TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions

  2013influential reference
• Neuroepithelial body microenvironment is a niche for a distinct subset of Clara-like precursors in the developing airways

  2012cited by this paper
• Expression of canonical WNT/β-CATENIN signaling components in the developing human lung

  2012cited by this paper
• Building and maintaining the epithelium of the lung.

  2012cited by this paper
• Genome‐scale study of transcription factor expression in the branching mouse lung

  2012cited by this paper
• A High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo

  2011cited by this paper
• Transcriptomic analysis of human lung development.

  2010cited by this paper
• HTII-280, a Biomarker Specific to the Apical Plasma Membrane of Human Lung Alveolar Type II Cells

  2010cited by this paper
• The NIH Roadmap Epigenomics Mapping Consortium

  2010cited by this paper
• A novel method for the generation of reaggregated organotypic cultures that permits juxtaposition of defined cell populations

  2009cited by this paper
• Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche

  2009cited by this paper
• Effect of Oxygen on the Expression of Hypoxia-Inducible Factors in Human Fetal Lung Explants

  2009influential reference
• The Id2+ distal tip lung epithelium contains individual multipotent embryonic progenitor cells

  2009cited by this paper
• Basal cells as stem cells of the mouse trachea and human airway epithelium

  2009cited by this paper
• Induction of a disintegrin and metalloprotease 33 during embryonic lung development and the influence of IL-13 or maternal allergy.

  2009cited by this paper
• edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

  2009influential reference
• Structure, expression, and biological function of INSM1 transcription factor in neuroendocrine differentiation

  2009cited by this paper
• Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists

  2008cited by this paper
• Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources

  2008cited by this paper
• A Gata6-Wnt pathway required for epithelial stem cell development and airway regeneration

  2008cited by this paper
• Expression of ABCA3 in Developing Lung and Other Tissues

  2007cited by this paper
• A global double‐fluorescent Cre reporter mouse

  2007cited by this paper
• The temporal and spatial distribution of ciliogenesis in the tracheobronchial airways of mice

  2005cited by this paper
• Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chain(null) mice.

  2005cited by this paper
• Nmyc plays an essential role during lung development as a dosage-sensitive regulator of progenitor cell proliferation and differentiation

  2005cited by this paper
• The NIH Roadmap

  2004cited by this paper
• Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells 12

  2004influential reference
• Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium.

  2000cited by this paper
• Transient effect of epidermal growth factor on the motility of an immortalized mammary epithelial cell line

  1999cited by this paper
• Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium.

  1999cited by this paper
• HTI56, an Integral Membrane Protein Specific to Human Alveolar Type I Cells

  1999cited by this paper
• Involvement of Sonic hedgehog (Shh) in mouse embryonic lung growth and morphogenesis.

  1997cited by this paper
• Evidence from normal expression and targeted misexpression that bone morphogenetic protein (Bmp-4) plays a role in mouse embryonic lung morphogenesis.

  1996cited by this paper
• Embryonic mouse lung epithelial progenitor cells co-express immunohistochemical markers of diverse mature cell lineages.

  1996cited by this paper
• EVIDENCE FROM NORMAL EXPRESSION AND TARGETED MISEXPRESSION THAT BONE MORPHOGENETIC PROTEIN-4 (BMP-4) PLAYS A ROLE IN MOUSE LUNG MORPHOGENESIS.• 1992

  1996cited by this paper
• Distribution of Fibroblast Growth Factor (FGF)-2 and FGF Receptor-1 Messenger RNA Expression and Protein Presence in the Mid-Trimester Human Fetus

  1996cited by this paper
• Temporal-spatial distribution of SP-B and SP-C proteins and mRNAs in developing respiratory epithelium of human lung.

  1994influential reference
• Developmental expression of SP-A and SP-A mRNA in the proximal and distal respiratory epithelium in the human fetus and newborn.

  1993cited by this paper
• Characterization of an antigenic determinant preferentially expressed by type I epithelial cells in the murine thymus.

  1992cited by this paper
• The role of the nonciliated bronchiolar epithelial (Clara) cell as the progenitor cell during bronchiolar epithelial differentiation in the perinatal rabbit lung.

  1992cited by this paper
• The transcription factor TTF-1 is expressed at the onset of thyroid and lung morphogenesis and in restricted regions of the foetal brain.

  1991cited by this paper
• Fetal and postnatal development of the lung.

  1984cited by this paper
• Developmental Study of a Lamellar Body Fraction Isolated From Human Amniotic Fluid

  1980cited by this paper
• Induction in vitro of tracheal buds by pulmonary mesenchyme grafted on tracheal epithelium.

  1962cited by this paper

• Spatial transcriptomics of developing human lungs defines cellular phenotypes associated with age, lineage and location

  2026cites this paper
• Research Advances and Disease Modeling in Respiratory Organoids

  2026cites this paper
• Dynamic in vitro platform for mechanical profiling of human pulmonary aciniform organoids via intraluminal access

  2026cites this paper
• Human Pluripotent Stem Cell-Derived Alveolar Organoids for Gene-editing and Lung Adenocarcinomas Modeling

  2025cites this paper
• A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease

  2025influential citation
• Applications of human lung organoids to human respiratory virus research: advances, limitations and future directions

  2025cites this paper
• Lung organoids as a human system for Mycobacteria infection modeling and drug testing.

  2025cites this paper
• Understanding and manipulating morphogenetic processes to generate in vitro models of airways.

  2025cites this paper
• Organoids from pluripotent stem cells and human tissues: When two cultures meet each other.

  2025cites this paper
• Modeling viral and bacterial infections in human lung organotypic systems reveals strain specific host responses

  2025cites this paper
• The Morphological, Behavioral, and Transcriptomic Life Cycle of Anthrobots

  2025cites this paper
• Predicting organoid morphology through a phase field model: Insights into cell division and lumenal pressure

  2025cites this paper
• SOXs: Master architects of development and versatile emulators of oncogenesis.

  2025cites this paper
• Emerging roles of epigenetic regulators during lung development

  2025cites this paper
• Cryopreservation of human lung tissue for 3D ex vivo analysis

  2025cites this paper
• Estrogenic effect, druglikeness, molecular docking, and pathway analysis of active compounds from fruit flour extract Rhizophora mucronate

  2025cites this paper
• Hypoxia promotes airway differentiation in the human lung epithelium

  2025cites this paper
• LIN28-mediated gene regulatory loops synchronize transitions throughout organogenesis

  2025cites this paper
• Bud, Branch, Breathe! Building a mammalian lung over space and time.

  2025cites this paper
• Progress in the application of organoids for exploring the relationship between macrophages and various lung diseases

  2025cites this paper
• Generation of Region-specific Airway Basal Stem Cells from Human Pluripotent Stem Cells via Regulation of BMP-NOGGIN Axis

  2025cites this paper
• Toxicity of Novel and Emerging Nicotine and Tobacco Products: A Review.

  2025cites this paper
• The pros and cons of mechanical dissociation and enzymatic digestion in patient-derived organoid cultures for solid tumor

  2024cites this paper
• Preclinical Models for Functional Precision Lung Cancer Research

  2024cites this paper
• The molecular and cellular choreography of early mammalian lung development

  2024cites this paper
• Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids

  2024cites this paper
• Epithelial-neuronal-immune cell interactions: implications for immunity, inflammation, and tissue homeostasis at mucosal sites.

  2024cites this paper
• Morphogenesis and regeneration share a conserved core transition cell state program that controls lung epithelial cell fate.

  2024cites this paper
• Development of an in vitro human alveolar epithelial air-liquid interface model using a small molecule inhibitor cocktail

  2024cites this paper
• Lung regeneration and lung bioengineering

  2024cites this paper
• In vitro modelling of bacterial pneumonia: a comparative analysis of widely applied complex cell culture models

  2024cites this paper
• The soluble factor milieu in idiopathic pulmonary fibrosis dysregulates epithelial differentiation

  2024cites this paper
• Protocol for the derivation and alveolar type 2 differentiation of late-stage lung tip progenitors from the developing human lungs

  2024cites this paper
• Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages.

  2024cites this paper
• Innovative explorations: unveiling the potential of organoids for investigating environmental pollutant exposure

  2024cites this paper
• Immune-Epithelial Cell Interactions in Lung Development, Homeostasis and Disease.

  2024cites this paper
• Liver organoids: updates on generation strategies and biomedical applications

  2024cites this paper
• Molecular distinctions of bronchoalveolar and alveolar organoids under differentiation conditions

  2024cites this paper
• Differentiation of CD166-positive hPSC-derived lung progenitors into airway epithelial cells

  2024cites this paper
• Modeling of the brain-lung axis using organoids in traumatic brain injury: an updated review

  2024cites this paper
• SOX on tumors, a comfort or a constraint?

  2024cites this paper
• High-parametric protein maps reveal the spatial organization in early-developing human lung

  2024cites this paper
• Physiological and immunological barriers in the lung

  2024cites this paper
• Organoids and organ-on-chip technology for investigating host-microorganism interactions.

  2024cites this paper
• Investigating pulmonary neuroendocrine cells in human respiratory diseases with airway models

  2024cites this paper
• Guidelines for Manufacturing and Application of Organoids: Lung

  2024cites this paper
• Integrative analysis of bulk and single-cell RNA sequencing reveals the gene expression profile and the critical signaling pathways of type II CPAM

  2024cites this paper
• Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

  2024cites this paper
• Complex in vitro models positioned for impact to drug testing in pharma: a review

  2024cites this paper
• An integrated single-cell reference atlas of the human endometrium

  2024cites this paper
• Discovering genes and microRNAs involved in human lung development unveils IGFBP3/miR-34a dynamics and their relevance for alveolar differentiation

  2024cites this paper
• Patient-derived tumor organoids: A preclinical platform for personalized cancer therapy

  2024cites this paper
• A novel method for generating induced pluripotent stem cell (iPSC)-derived alveolar organoids: a comparison of their ability depending on iPSC origin

  2023cites this paper
• Epithelial cells/progenitor cells in developing human lower respiratory tract: Characterization and transplantation to rat model of pulmonary injury

  2023cites this paper
• Contemporary and emerging technologies for research in children's rare and interstitial lung disease

  2023cites this paper
• Engineering and Modeling the Lung Mesenchyme.

  2023cites this paper
• Basic Science Perspective on Engineering and Modeling the Large Airways.

  2023cites this paper
• Innovative three-dimensional models for understanding mechanisms underlying lung diseases: powerful tools for translational research

  2023cites this paper
• Multipotent Embryonic Lung Progenitors: Foundational Units of In Vitro and In Vivo Lung Organogenesis.

  2023cites this paper
• hPSC-derived lung organoids: Potential opportunities and challenges

  2023cites this paper
• A distal lung organoid model to study interstitial lung disease, viral infection and human lung development

  2023cites this paper
• Single cell-guided prenatal derivation of primary epithelial organoids from the human amniotic and tracheal fluids

  2023cites this paper
• Human Lung Organoids—A Novel Experimental and Precision Medicine Approach

  2023cites this paper
• Simple Models of Lung Development.

  2023cites this paper
• Engraftment and injury repair in regionally conditioned rat lung in vivo by lung progenitors derived from human pluripotent stem cells

  2023cites this paper
• Primary human organoids models: Current progress and key milestones

  2023cites this paper
• Review of the British Thoracic Society Winter Meeting 23 November 2022 23–25 November 2022

  2023cites this paper
• Open questions in human lung organoid research

  2023cites this paper
• Epigenetic cues regulating airway development in human lung organoids: Polycomb repressive complex 2 and altered chromatin accessibility determine cell fate

  2023cites this paper
• A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

  2023cites this paper
• Lung patterning: Is a distal‐to‐proximal gradient of cell allocation and fate decision a general paradigm?

  2023cites this paper
• Alveolar Type 2 Epithelial Cell Organoids: Focus on Culture Methods

  2023cites this paper
• Recent advances in lung organoid development and applications in disease modeling

  2023influential citation
• Amniotic Fluid Organoids As Personalized Tools For Real-Time Modeling Of The Developing Fetus

  2023cites this paper
• Deterministic nuclear reprogramming of mammalian nuclei to a totipotency-like state by Amphibian meiotic oocytes for stem cell therapy in humans

  2023cites this paper
• Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors

  2023cites this paper
• A novel human fetal lung-derived alveolar organoid model reveals mechanisms of surfactant protein C maturation relevant to interstitial lung disease

  2023cites this paper
• Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung

  2023cites this paper
• Organotypic human lung bud microarrays identify BMP-dependent SARS- CoV-2 infection in lung cells

  2023influential citation
• Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung

  2023cites this paper
• The interplay between lumen pressure and cell proliferation determines organoid morphology in a multicellular phase field model

  2023cites this paper
• Single-cell RNA sequencing reveals the developmental program underlying proximal–distal patterning of the human lung at the embryonic stage

  2023cites this paper
• Alternative lung cell model systems for toxicology testing strategies: Current knowledge and future outlook.

  2023cites this paper
• Sox9 is associated with two distinct patterning events during snake lung morphogenesis.

  2023cites this paper
• Ex situ-armus: experimental models for combating respiratory dysfunction.

  2022cites this paper
• A Maverick Review of Common Stem/Progenitor Markers in Lung Development

  2022influential citation
• Microbiome as an immune regulator in health, disease, and therapeutics.

  2022cites this paper
• Disease modeling in organoid cultures: a new tool for studying viruses

  2022cites this paper
• The Patient-Derived Cancer Organoids: Promises and Challenges as Platforms for Cancer Discovery

  2022cites this paper
• Expandable Lung Epithelium Differentiated from Human Embryonic Stem Cells

  2022cites this paper
• Cancer Risk and Mutational Patterns Following Organ Transplantation

  2022cites this paper
• The benefits, limitations and opportunities of preclinical models for neonatal drug development

  2022cites this paper
• Application Progress of Organoids in Colorectal Cancer

  2022cites this paper
• Stable iPSC-derived NKX2-1+ lung bud tip progenitor organoids give rise to airway and alveolar cell types

  2022cites this paper
• Reconstructing the pulmonary niche with stem cells: a lung story

  2022cites this paper
• An essential function for autocrine hedgehog signaling in epithelial proliferation and differentiation in the trachea

  2022cites this paper
• Development of human alveolar epithelial cell models to study distal lung biology and disease

  2022cites this paper
• Three-dimensional models of the lung: past, present and future: a mini review.

  2022cites this paper
• Developmental origins of cell heterogeneity in the human lung

  2022cites this paper
• Human lung organoid: Models for respiratory biology and diseases.

  2022cites this paper