P06 - Distal lung cell circuit dynamics in reaction to toxic inhalation hazards

Lung disease accounts for one in six deaths globally. Most lung diseases cannot be cured. Therefore, curative options for lung disease are a huge unmet clinical need. Upon disruption of homeostasis through environmental challenges by toxic inhalation hazards, stem cells can regenerate the lung tissue by changing their internal transcriptional states and by coordinating their activities with a large number of other cells in their microenvironment. We hypothesize that the activation of different stem cell activities in response to injury is dependent on a highly concerted and integrated multicellular circuit that is currently poorly characterized. We develop methods that enable us to decipher routes of cell-cell communication manifesting these cell circuits in the terminal pulmonary acinus (terminal bronchiole, respiratory bronchioles, and alveoli) during injury and repair. We have recently identified an alveolar stem cell derived transitional intermediate stem cell state induced after bleomycin mediated lung injury1. In particular, for this project, we are interested in cell-cell communication of alveolar epithelial cell types (AT2/AT1) and the novel transitional alveolar epithelial cell state with the two specialized capillary endothelial cell populations (aCAP/gCAP)2. We would aim at understanding the molecular interactions of epithelial and endothelial cell states in injury repair. The main questions addressed will be:

• Which specific immediate transcriptional responses are initiated upon exposure to toxic agents in epithelial and endothelial cell types?
• How do cells influence each other during the regenerative response after acute lung injury?
• Which transcription factors are undergoing cell type specific activation during lung injury and repair?

The student will use an innovative ex vivo organotypic lung tissue culture model to study cell-cell communication between lineage labeled cell populations using highly multiplexed single cell perturbation experiments3,4. The work will be supervised daily by an experienced postdoc.

References

1. Strunz, M. et al. Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis. Nat. Commun. 11, 3559 (2020).
2. Gillich, A. et al. Capillary cell-type specialization in the alveolus. Nature 586, 785–789 (2020).
3. Datlinger, P. et al. Ultra-high throughput single-cell RNA sequencing by combinatorial fluidic indexing. doi:10.1101/2019.12.17.879304.
4. McGinnis, C. S. et al. MULTI-seq: sample multiplexing for single-cell RNA sequencing using lipid-tagged indices. Nat. Methods 16, 619–626 (2019).