Bone marrow mesenchymal stem cell-derived exosomes promote plasminogen activator inhibitor 1 expression in vascular cell
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RESEARCH
Open Access
Bone marrow mesenchymal stem cellderived exosomes promote plasminogen activator inhibitor 1 expression in vascular cells in the local microenvironment during rabbit osteonecrosis of the femoral head Lu Li1,2†, Yikai Wang1,3†, Xiaobing Yu2, Yongming Bao4, Lijia An4, Xiaowei Wei1, Weiting Yu1, Baoyi Liu1,2, Junlei Li1, Jiahui Yang1, Yan Xia5, Ge Liu1, Fang Cao1, Xiuzhi Zhang1 and Dewei Zhao1,2*
Abstract Background: Nontraumatic osteonecrosis of the femoral head (NONFH) is a highly disabling orthopedic disease in young individuals. Plasminogen activator inhibitor 1 (PAI-1) has been reported to be positively associated with NONFH. We aimed to investigate the dysregulating PAI-1 in bone marrow mesenchymal stem cells (BMMSCs) and vascular cells in rabbit steroid-induced NONFH. Methods: To verify the hypothesis that BMMSCs could promote thrombus formation in a paracrine manner, we collected exosomes from glucocorticoid-treated BMMSCs (GB-Exo) to determine their regulatory effects on vascular cells. microRNA sequencing was conducted to find potential regulators in GB-Exo. Utilizing gain-of-function and knockdown approaches, we testified the regulatory effect of microRNA in exosomes. Results: The expression of PAI-1 was significantly increased in the local microenvironment of the femoral head in the ONFH model. GB-Exo promoted PAI-1 expression in vascular smooth muscle cells and vascular endothelial cells. We also revealed that miR-451-5p in GB-Exo plays a crucial role for the elevated PAI-1. Moreover, we identified miR133b-3p and tested its role as a potential inhibitor of PAI-1. Conclusions: This study provided considerable evidence for BMMSC exosomal miR-mediated upregulation of the fibrinolytic regulator PAI-1 in vascular cells. The disruption of coagulation and low fibrinolysis in the femoral head will eventually lead to a disturbance in the microcirculation of NONFH. We believe that our findings could be of great significance for guiding clinical trials in the future. Keywords: Nontraumatic osteonecrosis of the femoral head, PAI-1, Bone marrow mesenchymal stem cells, Exosome, miRNA * Correspondence: [email protected] † Lu Li and Yikai Wang contributed equally to this work. 1 National-Local Joint Engineering Laboratory for the Development of Orthopedic Implant Materials, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, People’s Republic of China 2 Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article a
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