A three-dimensional model of human lung development and disease from pluripotent stem cells

Nat Cell Biol. 2017 May;19(5):542-549. doi: 10.1038/ncb3510. Epub 2017 Apr 24.

Abstract

Recapitulation of lung development from human pluripotent stem cells (hPSCs) in three dimensions (3D) would allow deeper insight into human development, as well as the development of innovative strategies for disease modelling, drug discovery and regenerative medicine. We report here the generation from hPSCs of lung bud organoids (LBOs) that contain mesoderm and pulmonary endoderm and develop into branching airway and early alveolar structures after xenotransplantation and in Matrigel 3D culture. Expression analysis and structural features indicated that the branching structures reached the second trimester of human gestation. Infection in vitro with respiratory syncytial virus, which causes small airway obstruction and bronchiolitis in infants, led to swelling, detachment and shedding of infected cells into the organoid lumens, similar to what has been observed in human lungs. Introduction of mutation in HPS1, which causes an early-onset form of intractable pulmonary fibrosis, led to accumulation of extracellular matrix and mesenchymal cells, suggesting the potential use of this model to recapitulate fibrotic lung disease in vitro. LBOs therefore recapitulate lung development and may provide a useful tool to model lung disease.

Publication types

  • Video-Audio Media

MeSH terms

  • Animals
  • Cell Culture Techniques*
  • Cell Differentiation
  • Cells, Cultured
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Lung / metabolism
  • Lung / pathology*
  • Lung / virology
  • Lung Transplantation
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice, Inbred NOD
  • Mutation
  • Organogenesis
  • Organoids / metabolism
  • Organoids / pathology*
  • Organoids / transplantation
  • Organoids / virology
  • Phenotype
  • Pluripotent Stem Cells / metabolism
  • Pluripotent Stem Cells / pathology*
  • Pluripotent Stem Cells / transplantation
  • Pluripotent Stem Cells / virology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Respiratory Syncytial Virus Infections / metabolism
  • Respiratory Syncytial Virus Infections / pathology*
  • Respiratory Syncytial Virus Infections / virology
  • Time Factors
  • Tissue Engineering / methods*

Substances

  • HPS1 protein, human
  • Membrane Proteins