Reprogramming lung epithelial cell lineages for regeneration

In chronic adult lung diseases both tissue homeostasis and repair are disrupted, regeneration mechanisms fail, and healthy cells are replaced with aberrant cells. My long-term vision is to overcome these problems in patients with early-stage lung disease by in vivo reprogramming of cell fate to induce regeneration and restore cellular homeostasis. To achieve this we will move beyond the current state-of-the-art for human lung cell culture and human lineage-tracing, employing new physiologically-mimetic culture methods optimised in my lab which allow the ecosystem of cell states present within a tissue to be interrogated together. Focusing on interstitial lung diseases, which are primarily caused by epithelial dysregulation, we will acquire the biological framework to test the hypothesis that intrinsic cell reprogramming can promote human lung regeneration. We will determine how the lineage-dynamics of complex airway epithelia vary with airway generation in development, homeostasis and chronic hypoxia, which is a consequence of multiple lung diseases. This crucial information will be pivotal for inducing cell fate transitions that follow naturally occurring cell lineages, which will be the most efficient and stable routes for reprogramming in the adult. In parallel, we will ‘decode’ lung cell fate by defining the gene regulation networks controlling differentiation, proliferation and quiescence of human lung epithelial cell types. This will allow us to predict, and functionally test, factors sufficient for cell fate reprogramming. These experiments will combine innovative human tissue models, novel genetic tools and systematic analyses of scRNA-seq data. These analyses of precise cell lineages and transcription factor codes will allow us to test whether in vivo reprogramming of cell fate to induce regeneration is feasible. Our data will also provide an essential framework for building advanced human tissue models.