scRNAseq on mouse lungs of bleomycin injured aged mice
Pulmonary fibrosis remains a significant public health concern due to an increasing incidence and limited treatment options. Alveolar type 2 epithelial cell (AT2) senescence causes stem cell exhaustion and progenitor failure, leading to ineffective and aberrant alveolar repairs and unresolved fibrosis. AT2 senescence regulatory molecules require additional studies. We demonstrate that the overexpression of syndecan-1 on IPF-AT2 cells is positively associated with the AT2 composite transcriptomic senescence score (SenMayo Senescence Score) and cellular senescence proteins. These findings imitate those of young and aged bleomycin-injured wild-type (WT) mice. The roles of syndecan-1 in regulating AT2 cellular senescence are corroborated in human and mouse lung epithelial cell lines. Functionally, the AT2 alveolospheres from bleomycin-injured Sdc1–/– mice had higher colony-forming efficiency (CFE) and normal differentiation, whereas WT alveolospheres were less proliferative and aberrant differentiation. Using precision-cut lung slices (PCLS), bleomycin-injured WT lungs had lower AT2 cells and a lower secretory surfactant protein C than Sdc1–/– PCLS, indicating the detrimental role of excess syndecan-1.  We further showed that the transcriptomic p53 activity score is higher in IPF and bleomycin-injured WT AT2 cells compared to Sdc1–/– AT2 cells. Additionally, syndecan-1 activated p53 by inducing acetylation at lysine379. Our work indicates that syndecan-1 reprograms AT2 cells to become senescent during lung fibrogenesis and likely through the p53 signaling pathway. Overall design: 18-24 months old wild type and Sdc1 knockout mice were subjected to bleomycin injury. Lung tissue are reovered at different timepoints including day 14, 28 and 56.