Human Urine Stem Cells Alleviate Pulmonary Fibrosis via Inhibiting Macrophage‐Myofibroblast Transition

Human Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with unknown etiology and lacking efficient treatments. Here, we reported that human urine stem cells (hUSCs) significantly alleviated pulmonary fibrosis via inhibiting macrophage-myofibroblast transition (MMT), which was identified as a pivotal pathological process in IPF, with the strong interaction among infiltrated macrophages, damaged alveolar epithelial cells, and myofibroblasts via single-nucleus RNA sequencing data analysis and co-immunostaining. In addition, hUSCs significantly alleviated pulmonary fibrosis by attenuating alveolar epithelial cell damage, reducing monocyte-derived macrophage infiltration, and suppressing MMT in the bleomycin-induced pulmonary fibrosis mouse model. Furthermore, we demonstrated hUSCs inhibited monocyte recruitment and MMT via paracrine actions in the macrophage-alveolar epithelial cell co-culture system. Mechanistically, DKK1, which was highly secreted by hUSCs and identified by Venn diagram analysis between the luminex assay in supernatants of THP1 treated with hUSC-CM and antibody array of hUSC-CM, might contribute to preventing MMT via suppressing the Wnt/β-catenin signaling pathway in macrophages. In summary, hUSCs exerted multifaceted protective effects against pulmonary fibrosis, at least in part through paracrine mechanisms involving DKK1 and its modulation of Wnt/β-catenin-associated fibrotic responses in MMT. Therefore, hUSCs might provide a potential therapeutic strategy for IPF clinically.