When the lungs regenerate after an illness or environmental-related diseases, there are a number of cell differentiation processes whose molecular details have not yet been fully understood. Researchers of the DZL site Munich (CPC-M) and the ICB (Helmholtz Center Munich) have discovered a new stem cell state and been able to decode cellular hierarchy during alveolar regeneration following injury. The findings of their work have been published in Nature Communications.
Lung diseases account for one-sixth of deaths worldwide. Due to its surface, the lung epithelium is particularly susceptible to microbial and environmentally caused damage. Various stem cell populations can repair this damage by replacing the damaged cells. In the process of cell differentiation, stem cells change their gene activities and hence, in the long term, also their identity. Molecular control and dynamics of such processes have scarcely been examined so far. Using time-resolved single-cell transcriptomics and lineage tracing, the team of Herbert Schiller (CPC-M) and Fabian Theis (ICB) has now been able to partially decode cellular hierarchy during alveolar regeneration (pulmonary alveoli) following injury.
Together with their colleagues, scientists of the Institutes for Lung Biology and Disease as well as Computational Biology analyzed the course of cell differentiation processes for 28 different types of cells and compiled a map with single-cell RNA sequencing data of cell state changes during lung regeneration. Here, they found that, in pulmonary fibrosis, a particular transitional state is abnormally regulated. This fault in the course of the regeneration process might possibly be the cause for developing the disease. These findings provide a significant molecular basis for developing future therapies.
“In order to reprogram cells in the pathologically modified lung back to “normal”, we must first gain an understanding of the process and control of cell state change in the course of normal recovery. Our data suggest that certain regenerative stem cell states in the scarred lungs of patients with pulmonary fibrosis persist chronically,” suggests Dr. Herbert Schiller, head of the study.
Further studies to unveil the exact mechanism of the newly discovered stem cell state in the pathogenesis of fibrosis are already underway.
During lung regeneration, alveolar stem cells (red) change their shape and turn into flat al-veolar epithelial cells (green).
© Helmholtz-Center Munich
Schiller H. et al, nature communications, 2020: Alveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis.