1.5 IPF
IPF is a deadly respiratory disease that mainly occurs in middle-aged and elderly people [35]. It is an interstitial disease in which fibroblast expansion occurs in parallel with excessive production and deposition of extracellular matrix, leading to airway remodeling, inflammation, alveolar destruction, and fibrosis [36]. Currently, many scRNA-seq studies have provided new insights into the cell types and cell interaction-related biological processes involved in IPF pathogenesis. Barry R Strip et al. [37] mapped epithelial cell types in normal and IPF airways by scRNA-seq and revealed the reconstruction of IPF basal cell diversity. Taylor S. Adams et al. [38] constructed a single-cell atlas of IPF that focued on aberrant epithelial, fibroblast,and endothelial cell populations, and identified all known lung epithelial cell populations in control samples, including alveolar type 1 (AT1) and type 2 (AT2) cells, ciliated cells, basal cells, goblet cells, club cells, pulmonary neuroendocrine cells, ionocytes, and 80 aberrant basaloid cells. The occurrence of IPF is closely related to alveolar epithelial injury. ScRNA-seq of IPF lung tissues revealed that matrix metalloproteinase 7 (MMP7), integrin αVβ6, cellular senescence, and epithelial-mesenchymal transition (EMT) abnormal epithelial cells were highly expressed at the edges of fibroblastic lesions, whereas they were not present in normal lung tissues, which once again suggests that the development of IPF is closely related to alveolar epithelial damage. This is because dysfunctional epithelial cells interact with mesenchymal cells, immune cells, and endothelial cells via various signaling mechanisms which trigger the activation of fibroblasts and myofibroblasts, whereas abnormal NOTCH2+ basal cells are susceptible to metabolic dysfunction, aberrant epithelial activation, and epithelial repair dysfunction [39]. Fibroblasts are the central mediators of extracellular matrix production in IPF. Rebecca Peyser et al. [40] identified 49 signature genes and delineated fibroblast subpopulations by scRNA-seq techniques. They found that fibroblast activation was poorly correlated with the expression of transforming growth factor-β pathway genes. The immune microenvironment involved in IPF has now been revealed by use of scRNA-seq technology. Those studies showed that macrophages around the lesion secrete a type 1 phosphorylated protein (SPP1) that causes organ fibrosis, and that the T cells involved in anti-fibrotic and pro-fibrotic activates are mainly Th9, Th22, and γδT cells [37]. It is self-evident that fibroblasts, epithelial cells, and immune cells do not independently influence the formation and development of IPF. A combination of biological approaches, as well as in vivo modeling will provide important data regarding the transcriptomic changes and cellular interactions associated with IPF development, and those data will need to be further validated by measurements of gene and protein expression.