Dissecting pulmonary fibroblasts heterogeneity in lung development, health and diseases

Lung fibroblasts are the major components in the connective tissue of the pulmonary interstitium and play essential roles in the developing of postnatal lung, synthesizing the extracellular matrix and maintaining the integrity of the lung architecture. Fibroblasts are activated in various disease conditions and exhibit functional heterogeneities according to their origin, spatial location, activated state and microenvironment. In recent years, advances in technology have enabled researchers to identify fibroblast subpopulations in both mouse and human. Here, we discuss pulmonary fibroblast heterogeneity, focusing on the developing, healthy and pathological lung conditions. We firstly review the expression profiles of fibroblasts during lung development, and then consider fibroblast diversity according to different anatomical sites of lung architecture. Subsequently, we discuss fibroblast heterogeneity in genetic lineage. Finally, we focus on how fibroblast heterogeneity may shed light on different pathological lung conditions such as fibrotic diseases, infectious diseases including COVID-19, and lung cancers. We emphasize the importance of comparative studies to illuminate the overlapping characteristics, expression profiles and signaling pathways of the fibroblast subpopulations across disease conditions, a better characterization of the functional complexity rather than the expression of a particular gene may have important therapeutic applications.