Office of Technology Transfer – University of Michigan

Methods for Converting Stem Cells Into 3D Lung Tissues Through Directed Differentiation

Technology #6573

Currently, there is a challenge in studying organ development and organ diseases. In vivo animal models are time consuming, difficult to study, and often don’t directly mimic a human organ system. Therefore, there has been a drive to create an in vitro model that better resembles a human system. Scientists have been able to drive human pluripotent stem cells (hPSCs) in to specific organ cell lineages. However, in organ systems like the lung, most research on differentiating hPSCs has been done on a two-dimensional model. These models lack proper cell morphology, multiple tissue types, and proper structure of an actual human organ. This technology outlines a specific process to drive hPSCs into a three-dimensional human lung organoid (HLO) that more accurately mimics a human fetal lung. This technology could provide a novel in vitro model system for the study of lung development and lung diseases.

Novel Method for Producing HLOs Through Directed Differentiation of hPSCs

These HLOs can be produced utilizing embryonic and induced hPSCs. Differentiation is done through manipulation of several signaling events such as the inhibition of BMP and TGFβ signaling. The correct combination of small molecule inhibitors and growth factors at key differentiation stages drives the hPSC in to an endoderm and then in to an anterior foregut spheroid, which is what the lung is developed from. This process blocks other organ lineages, such as an intestinal lineage, and ensures the production of lung tissue. These spheroids can be manipulated further by activation of hedgehog signaling to induce an HLO. These HLO contain a complex tissue structure including proximal and distal-like tissue along with mesenchyme. They also contain alveolar like structures similar to the human fetal lung. This method provides a reliable system for the induction of HLOs from hPSCs that can be propagated in culture for up to 100 days. These HLOs have the potential to be a unique and useful in vitro model for research use.

Applications

  • In vitro lung model for developmental and disease research
  • Stem cell culture differentiation media
  • Model to assess potential drug targets for lung diseases and cancer

Advantages

  • 3D lung organoid rather than 2D
  • Mimics human fetal lung
  • Contains complex and differing tissue types rather than just one
  • Structurally and morphologically similar to the human fetal lung
  • Contains alveolar-like structures