Affiliation:
1. Ningxia Clinical Research Institute Center Laboratory, People's Hospital of Ningxia Hui Autonomous Region Yinchuan China
2. Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western College of Life Science, Ningxia University Yinchuan China
3. General Hospital of Ningxia Medical University Yinchuan Ningxia China
4. Zephyrm Biotechnologies Co., Ltd. Beijing China
5. Department of Anatomy and Cell Biology Carver College of Medicine, University of Iowa Iowa City Iowa USA
Abstract
AbstractSilicosis is an irreversible chronic pulmonary disease caused by long‐term inhalation and deposition of silica particles, which is currently incurable. The exhaustion of airway epithelial stem cells plays a pathogenetic role in silicosis. In present study, we investigated therapeutic effects and potential mechanism of human embryonic stem cell (hESC)‐derived MSC‐likes immune and matrix regulatory cells (IMRCs) (hESC‐MSC‐IMRCs), a type of manufacturable MSCs for clinical application in silicosis mice. Our results showed that the transplantation of hESC‐MSC‐IMRCs led the alleviation of silica‐induced silicosis in mice, accompanied by inhibiting epithelia‐mesenchymal transition (EMT), activating B‐cell‐specific Moloney murine leukemia virus integration site 1 (Bmi1) signaling and airway epithelial cell regeneration. In consistence, the secretome of hESC‐MSC‐IMRC exhibited abilities to restore the potency and plasticity of primary human bronchial epithelial cells (HBECs) proliferation and differentiation following the SiO2‐induced HBECs injury. Mechanistically, the secretome resolved the SiO2‐induced HBECs injury through the activation of BMI1 signaling and restoration of airway basal cell proliferation and differentiation. Moreover, the activation of BMI1 significantly enhanced the capacity of HBEC proliferation and differentiation to multiple airway epithelial cell types in organoids. Cytokine array revealed that DKK1, VEGF, uPAR, IL‐8, Serpin E1, MCP‐1 and Tsp‐1 were the main factors in the hESC‐MSC‐IMRC secretome. These results demonstrated a potential therapeutic effect of hESC‐MSC‐IMRCs and their secretome for silicosis, in part through a mechanism by activating Bmi1 signaling to revert the exhaustion of airway epithelial stem cells, subsequentially enhance the potency and plasticity of lung epithelial stem cells.
Funder
National Natural Science Foundation of China
Subject
Health, Toxicology and Mutagenesis,Management, Monitoring, Policy and Law,Toxicology,General Medicine