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

ABSTRACT 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.