Deciphering the role of fibrosis-specific alveolar basal cells in idiopathic pulmonary fibrosis

Blumer, Sabrina. Deciphering the role of fibrosis-specific alveolar basal cells in idiopathic pulmonary fibrosis. 2023, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/96074/

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Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and irreversible interstitial lung disease characterized by progressive destruction of the lung parenchyma and loss of lung function. The cause is unknown, but it is believed that repetitive epithelial injuries and impaired healing contribute to its pathogenesis. In IPF, a maladaptive repair mechanism occurs, where alveolar epithelial cell type 2 (AT2) cells are depleted and ectopic basal cells (BC) accumulate within the alveolar region. These alveolar BC may arise from trans-differentiation of resident AT2 cells triggered by the fibrotic environment, migration as "classical" BC from the airways into the injured alveoli, or a combination of both mechanisms. Their precise role in IPF is incompletely understood; some studies suggest a regenerative potential in animal models, while others associate them with increased mortality, pathological bronchiolization and honeycomb cyst (HC) formation. Given the limited efficacy of current anti-fibrotic treatments and lung transplantation as the only long-term survival option, this thesis aims to decipher the characteristics and functional role of fibrosis-specific alveolar BC, with the goal of working towards innovative therapeutic approaches for IPF patients.
While the increased presence of alveolar BC in IPF lung parenchyma implies a causative role in the fibrogenesis, our findings in publication I revealed a significant anti-fibrotic impact of their secretome, effectively inhibiting aberrant fibroblast activation and differentiation in IPF.
In publication II, we highlighted the ability of cultured alveolar BC to differentiate into secretory-like cells and aberrant basaloid-like cells using single cell RNA sequencing, with a remarkable potential for reversing this process through microenvironment changes.
In the manuscript, we optimized in vitro and in vivo models including submerged, air-liquid interface, organoid culture and a bleomycin-induced mouse model using patient-derived alveolar BC. These models mimic HC-like structures observed in IPF, representing powerful tools to study HC formation and its potential pharmacological inhibition.
Our unpublished data comparing alveolar to airway BC from the same patients revealed distinct transcriptomic differences and varying responses to in vitro microenvironments, offering promise for developing targeted drugs against alveolar BC in IPF. Although alveolar BC can partially transform into surfactant protein-expressing cells using a specific cocktail, achieving full AT2 cell differentiation remains elusive. Directing alveolar BC differentiation into AT2 cells represents an attractive target to facilitate IPF lung regeneration.
Taken together, while alveolar BC may provide temporary support in preserving alveolar integrity during acute injury, their persistence could impede effective lung regeneration and contributes to pathological HC formation. These insights advance the development of translational approaches for future treatments in IPF patients.
Advisors:Hostettler , Katrin
Committee Members:Affolter, Markus and Simon, Hans Uwe
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Growth & Development > Cell Biology (Affolter)
UniBasel Contributors:Hostettler, Karin and Affolter, Markus
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15197
Thesis status:Complete
Number of Pages:182
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss151977
edoc DOI:
Last Modified:16 Dec 2023 05:30
Deposited On:15 Dec 2023 10:52

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