Building blocks for lung regeneration: Stem cells and niches.

The respiratory system is an essential organ that performs gas exchange through the blood circulation in mammals. Unlike other organs, the lungs are directly exposed to the external environment, including particulate matter, cigarette smoke, and various pollutants, and are therefore, highly susceptible to damage. The lungs retain regional-specific stem/progenitor cells that quickly mobilize to replace the damaged epithelium. Accumulating evidences suggest that fate decision of stem cells relies on regulatory programs integrated by niches constituting the microenvironment providing diverse signals that regulate stem cell behavior. Therefore, understanding cellular diversity and precise interaction between stem cells and their respective niches is crucial to understand how tissue recovers homeostasis after injury. Here, in this review, we summarize recent progress in cellular and functional identity of stem cells and distinctive niches in the lungs. We also describe the molecular mechanism of genetic and epigenetic program in the regulation of stem cell behavior during tissue regeneration. Lastly, we introduce the three-dimensional lung organoid platforms that provide valuable insights into the mechanisms of lung pathophysiology in human system.