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

Marko Z Nikolić, Oriol Caritg, Quitz Jeng, Jo-Anne Johnson, Dawei Sun, Kate J Howell, Jane L Brady, Usua Laresgoiti, George Allen, Richard Butler, Matthias Zilbauer, Adam Giangreco, Emma L Rawlins

Research output: Contribution to journalArticlepeer-review

188 Citations (Scopus)

Abstract

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.

Original languageEnglish
JournaleLife
Volume6
DOIs
Publication statusPrint publication - 30 Jun 2017
Externally publishedYes

Keywords

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Humans
  • Lung/cytology
  • Mice
  • Organoids/growth & development
  • Respiratory Mucosa/cytology
  • Stem Cells/physiology

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