Identifying TNFSF4(low)-MSCs superiorly treating idiopathic pulmonary fibrosis through Tregs differentiation modulation.

BACKGROUND: Idiopathic pulmonary fibrosis is a progressive lung disorder, presenting clinically with symptoms such as shortness of breath and hypoxemia. Despite its severe prognosis and limited treatment options, the pathogenesis of idiopathic pulmonary fibrosis remains poorly understood. This study aims to investigate the therapeutic potential of mesenchymal stromal cells in treating idiopathic pulmonary fibrosis, focusing on their ability to modulate regulatory T cells through the low tumor necrosis factor superfamily member 4 (TNFSF4) pathway. The goal is to identify mesenchymal stromal cells subtypes with optimal immunomodulatory effects to enhance regulatory T cells functions and ameliorate fibrosis. METHODS: We identified the immune characteristics of idiopathic pulmonary fibrosis by mining and analyzing multiple public datasets and detecting regulatory T cells in the blood and lung tissues of idiopathic pulmonary fibrosis patients. An extensive examination followed, including assessing the impact of mesenchymal stromal cells on regulatory T cells proportions in peripheral blood and lung tissue, and exploring the specific role of TNFSF4 expression in regulatory T cells modulation. Whole-genome sequencing and cluster analysis were used to identify mesenchymal stromal cells subtypes with low TNFSF4 expression. RESULTS: Mesenchymal stromal cells characterized by TNFSF4 expression (TNFSF4(low)-MSCs) demonstrated enhanced ability to regulate regulatory T cells subpopulations and exhibited pronounced anti-fibrotic effects in the bleomycin-induced idiopathic pulmonary fibrosis mouse model. These mesenchymal stromal cells increased regulatory T cells proportions, reduced lung fibrosis, and improved survival rates. TNFSF4-tumor necrosis factor receptor superfamily member 4 (TNFRSF4) signaling was identified as a critical pathway influencing regulatory T cells generation and function. CONCLUSIONS: Our findings underscore the pivotal role of TNFSF4 in mesenchymal stromal cells mediated regulatory T cells modulation and highlight the therapeutic potential of selecting mesenchymal stromal cells subtypes based on their TNFSF4 expression for treating idiopathic pulmonary fibrosis. This approach may offer a novel avenue for the development of targeted therapies aimed at modulating immune responses and ameliorating fibrosis in idiopathic pulmonary fibrosis. TRIAL REGISTRATION: Our study involved collecting 10 mL of peripheral blood from idiopathic pulmonary fibrosis patients, and the Medical Ethics Committee of Nanjing Drum Tower Hospital approved our study protocol with the approval number 2023-675-01.