Cellular and Molecular Plasticity of Alveolar Stem Cells in Pulmonary Fibrosis

Abstract

Pulmonary Fibrosis (PF) is a devastating disease characterized by excessive fibrotic scarring in the lungs, leading to a significant global mortality rate. Despite its increasing incidence, early detection and treatment remain challenging due to the complexity of the disease. Therefore, it need to understand the cellular and molecular mechanisms underlying fibrosis development, leading to the advance in therapeutic strategies. This study aims to identify the cellular and molecular plasticity of alveolar stem cells, particularly alveolar type II (AT2) cells, in fibrosis. To this end, we have first characterized the AT2 cells in the lungs of normal donor and patients diagnosed as idiopathic pulmonary fibrosis. While AT2 cells in the lungs of early IPF patients show similar expression of canonical markers for stem cells such as SPC (surfactant protein C), they exhibited altered morphology and genetic signatures with higher expression of genes that are only expressed in airway lineage cells, indicating a loss of AT2 cell identity. We then examined whether AT2 cells in the lungs of IPF patients retain the regenerative capacity to maintain the alveolar lineages. To this end, we established lung organoid derived from normal donors or patients diagnosed with IPF especially at the early stage of disease. While AT2 cells from normal donors show the stem cell activity of self-renewal and differentiation of alveolar lineages, AT2 cells derived from early IPF patients showed altered plasticity to differentiate into airway lineage cells that are prominent in the parenchyma of IPF lungs. This result suggests that altered plasticity of stem cells may impair the regeneration and lead to the development of fibrosis. Overall, this study indicates the defects of plasticity of alveolar stem cells in the lungs of fibrosis patients, implicating the impact of defective regeneration on the development of pulmonary fibrosis. This research may provide valuable insights into the key regulatory pathway modulating the lung regeneration program and facilitate the development of the novel therapeutic approaches for pulmonary fibrosis.