Secretome of hESC-Derived MSC-like Immune and Matrix Regulatory Cells Mitigate Pulmonary Fibrosis through Antioxidant and Anti-Inflammatory Effects
Wenfeng Hu,
Jiali Yang,
Jing Xue,
Jia Ma,
Shuang Wu,
Jing Wang,
Ranran Xu,
Jun Wei,
Yujiong Wang,
Shuyan Wang,
Xiaoming Liu
Affiliations
Wenfeng Hu
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Jiali Yang
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Jing Xue
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Jia Ma
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Shuang Wu
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Jing Wang
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Ranran Xu
Zephyrm Biotechnologies Co., Ltd., Beijing 102200, China
Jun Wei
Zephyrm Biotechnologies Co., Ltd., Beijing 102200, China
Yujiong Wang
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
Shuyan Wang
Zephyrm Biotechnologies Co., Ltd., Beijing 102200, China
Xiaoming Liu
Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources of Western China, College of Life Science, Ningxia University, Yinchuan 750021, China
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.
