Beyond the epithelium: multicellular niches in lung regeneration and disease

Pulmonary homeostasis and regeneration require coordination between epithelial cells, immune populations, vascular networks, extracellular matrix, and stromal cells. This mini review examines recent advances in lung niche biology that were a focus of the 2025 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference. Here, we emphasize the impact of nonepithelial compartments essential for tissue function and repair. Reflecting the conference's emphasis on comprehensive niche biology, we highlight how nonepithelial compartments, including stromal, vascular, and immune cells, serve as essential regulators of tissue function and repair, a perspective that unified many of the presentations and discussions. In diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease, disruption of these niche interactions, rather than isolated cellular defects, drives regenerative failure. Spatial transcriptomic approaches reveal how pathological cell states colocalize within aberrant microniches. These insights suggest that effective therapeutics must target entire multicellular ecosystems, with advanced organoid platforms offering promising tools for developing niche-modulating interventions.