Secretome of hESC-Derived MSC-like Immune and Matrix Regulatory Cells Mitigate Pulmonary Fibrosis through Antioxidant and Anti-Inflammatory Effects

Oxidative stress and inflammation are major drivers in the pathogenesis and progression of pulmonary fibrosis (PF). The mesenchymal stem cell (MSC) secretome has regenerative potential and immunomodulatory functions. Human embryonic stem cell (hESC)-derived MSC-like immune and matrix regulatory cells (IMRCs) are manufacturable with large-scale good manufacturing practice (GMP) preparation. In the present study, the antioxidative and anti-inflammatory properties and the therapeutic effect of the secretome of hESC-MSC-IMRC-derived conditioned culture medium (CM) (hESC-MSC-IMRC-CM) were investigated. Results revealed the capacities of hESC-MSC-IMRC-CM to reduce bleomycin (BLM)-induced reactive oxygen species (ROS), extracellular matrix (ECM) deposition, and epithelial-mesenchymal transition (EMT) in A549 cells. The administration of concentrated hESC-MSC-IMRC-CM significantly alleviated the pathogenesis of PF in lungs of BLM-injured mice, as accessed by pathohistological changes and the expression of ECM and EMT. A mechanistic study further demonstrated that the hESC-MSC-IMRC-CM was able to inhibit BLM-induced ROS and pro-inflammatory cytokines, accompanied by a reduced expression of Nox4, Nrf2, Ho-1, and components of the Tlr4/MyD88 signaling cascade. These results provide a proof of concept for the hESC-MSC-IMRC-derived secretome treatment of PF, in part mediated by their antioxidative and anti-inflammatory effects. This study thus reinforces the development of ready-to-use, cell-free hESC-MSC-IMRC secretome biomedicine for the treatment of PF in clinical settings.

Automated summary

This study investigated the antioxidative and anti-inflammatory properties of the secretome of human embryonic stem cell-derived mesenchymal stem cell-like immune and matrix regulatory cells (IMRCs) and its therapeutic effect on pulmonary fibrosis. The results showed that the IMRC secretome could reduce oxidative stress, extracellular matrix deposition, and epithelial-mesenchymal transition in lung cells. Administering the concentrated IMRC secretome effectively alleviated pulmonary fibrosis in mice, likely through inhibiting oxidative stress and inflammation. This study provides evidence for the development of cell-free IMRC secretome therapy for pulmonary fibrosis in clinical settings.