Human mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis in humanized mice

Abstract

Pulmonary fibrosis is a chronic, progressive and refractory disease, characterized by activation of myofibroblast followed by extensive extracellular matrix (ECM) deposition. It finally results in disruption of pulmonary function and decrease of exercise tolerance. Despite numerous effects made by researchers, the pathogenesis of pulmonary fibrosis remains elusive. So far, there is no proven effective therapy for pulmonary fibrosis. Human mesenchymal stem cells (MSC) have been investigated for their therapeutic potential in pulmonary fibrosis. Although the feasibility and the safety of human MSC administration in patients with pulmonary fibrosis have been proved in Phase 1b clinical trials, the therapeutic efficacy is waiting to be assessed. Previous studies indicated the immunomodulatory capacity of human MSC could benefit the attenuation of pulmonary fibrosis. However, most of the studies were performed in vitro and in the conventional murine model, of which the suggestive value is limited. In this study, we established the humanized mice that were constituted with human peripheral blood mononuclear cells (PBMC). This model facilitates the direct investigation of human cell interaction in animal models. Based on this model, we assess the modulatory effect of human MSC on human immune cells and the therapeutic efficacy of human MSC on bleomycin-induced pulmonary fibrosis. Our result showed human MSC could alleviate pulmonary fibrosis and improve lung function by suppressing bleomycin-induced human T lymphocyte infiltration and pro-inflammatory cytokine production in the lungs of humanized mice. Furthermore, the programmed death-ligand 1 (PD-L1)- and the indoleamine 2,3-dioxygenase (IDO)-mediated immunosuppressive pathways were found to be involved in the attenuation of pulmonary fibrosis by human MSC. In the following clinical investigation of the patients with pulmonary fibrosis in this study, the aberrant pulmonary lymphocyte infiltration and the abnormal expressions of programmed death-1 (PD-1) and IDO in lungs and peripheral blood were also observed in patients with pulmonary fibrosis. This study expands the understanding of the pathogenesis of pulmonary fibrosis and provides evidence to support the potential therapeutic value of human MSC in this disease.