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Elucidate the mechanisms driving reprogramming in lung regeneration

Supervisor: Joo-Hyeon Lee

Lungs are slow turnover organs that are highly quiescent at steady-state. However, the lung has a tremendous ability to repair epithelial damage following injury and contains multiple, highly plastic, stem cell populations. The airway epithelial club (Scgb1a1+) cells have long been thought to be stem cells that maintain airways in homeostatic condition, but generate alveolar lineages upon bleomycin-induced alveolar injury. Furthermore, it was recently shown that upon depletion of basal cells that are stem cell populations in proximal airways, Scgb1a1+ club cells can dedifferentiate into basal cells that have the full capability of redifferentiation into secretory as well as ciliated epithelial lineages. These findings dictate dramatic epithelial cell–lineage switching upon injury in the lung. However, the signals that regulate plasticity mechanisms in these cell compartments are yet to be fully determined.

In this project, we will ask important questions: what mechanisms regulate the transition of cells from quiescent to dividing and back again? how is epithelial cell–lineage switching/de-differentiation normally restricted during lung homeostasis? Finally, what are the mechanisms that drive this process?

We hypothesise that cell fate is not permanently locked in adult lung epithelial cells and that manipulating such fate decisions could promote repair and regeneration. We will define discreet stem and progenitor cell populations that have flexibility to switch lineages using single cell RNA- Seq during injury repair. Behavioral heterogeneity of these populations during tissue regeneration and molecular mechanisms underlying lineage specification regulation will be also determined using in vitro organoid system and in vivo lineage tracing techniques combined with CRISPR-mediated gene modification.

Relevant references

Lee JH, Tammela T, Hofree M, Choi J, Marjanovic ND, Han S, Canner DA, Wu K, Paschini M, Bhang DH, Jacks T, Regev A, Kim CF (2017). Anatomically and functionally distinct lung mesenchymal populations marked by Lgr5 and Lgr6. Cell. 170(6):1149-1163.

Choi J, Iich E, Lee JH (2016) Organogenesis of adult lung in a dish: Differentiation, disease and therapy. Dev Biol. 420(2):278-286.

Lee JH, Bhang DH, Beede A, Huang TL, Stripp B, Bloch KD, Wagers AJ, Tseng YH, Ryeom S, Kim CF (2014) Lung stem cell differentiation in mice directed by endothelial cells via a BMP4-NFATc1-Thrombospondin-1 axis. Cell. 156(3):440-55.