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Elife. 2017 Jun 30;6. pii: e26575. doi: 10.7554/eLife.26575.

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

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Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge, United Kingdom.
Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, United Kingdom.
Department of Paediatric Gastroenterology, University of Cambridge and Addenbrookes Hospital, Cambridge, United Kingdom.
Lungs for Living Research Centre, UCL Respiratory, University College London, London, United Kingdom.
Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Wellcome Trust/MRC Stem Cell Institute, Cambridge, United Kingdom.


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.


alveolar differentiation; branching; developmental biology; human; human biology; lung development; medicine; stem cell; stem cells; tip progenitor

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