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How the lungs' alveolar surface regenerates

The molecular details of stem cell differentiation in the lung, which is induced as a response to injury caused by microbial and environmental challenges, are not well characterised. Researchers at the ILBD/CPC and ICB (Helmholtz Zentrum München) have discovered a new stem cell state and were able to decipher the cellular hierarchy during regeneration of the lungs alveoli after injury. The results of their work have now been published in Nature Communications.

(click to see bigger picture) During lung regeneration the alveolar stem cells (red) undergo a drastic shape change and become flat alveolar epithelial cells (green). © Helmholtz Zentrum München

Lung diseases are responsible for one-sixth of all deaths worldwide. Due to its large surface area, the alveolar epithelium is a prime target for microbial and environmental insults. Different stem cell populations are capable of repairing the injury by replacing the damaged cells. In the process of cell differentiation, the stem cells change their gene activities and thus their long-term identity. The molecular control and dynamics of such processes are currently insufficiently studied. Using time-resolved single-cell transcriptomics and lineage tracing, the team led by Herbert Schiller and Fabian Theis has now been able to revise the current knowledge about the cellular hierarchy during regeneration of the lungs alveoli following injury.

The scientists from the Institutes of Lung Biology and Disease and Computational Biology and their colleagues investigated the course of the cell differentiation processes for 28 different cell types. Using single cell RNA-seq, they created a map of the cell state changes during lung regeneration. In doing so, they found that a novel transitional stem cell state is abnormally regulated in pulmonary fibrosis. This error in the course of the regeneration process may be responsible for the development of the disease.

The result will provide an important molecular basis for the development of future therapies. "In order to be able to reprogram the cells in the pathologically altered lung back to 'normal' in the future, we must first understand the sequence and control of cell state changes during the course of normal recovery. Our data suggest that certain regenerative stem cell states in the scarred lung of patients with pulmonary fibrosis persist chronically," explains Dr. Herbert Schiller, the study's leader.

Further investigations are already underway to identify the exact mechanism of the newly discovered stem cell state in the pathogenesis of fibrosis.

Link to the publication in nature communications:

As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus, allergies and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,500 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 19 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. 

The Comprehensive Pneumology Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität Clinic Complex and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is a site of the Deutsches Zentrum für Lungenforschung (DZL).