Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages

Kanglu Li,Bo Zhu,Ke Ma,Dejie Lu,Guohua Yan,Mingjun Zheng,Jinmin Zhao,Xiaofei Cui,Hanji Huang,Jianwen Cheng,Li Zheng

doi:10.1186/s12951-021-01236-1

Abstract

Osteoarthritis (OA) is a degenerative illness that greatly impacts the life quality of patients. Currently, the therapeutic approaches for OA are very limited in clinical. The extracellular vesicles (EVs) derived from different mesenchymal stem cells displayed a prominent therapeutic effect on OA. But most EVs have limited resources and the risks of host rejection, immunological response, and etc. Human umbilical cord mesenchymal stem cells (hUCMSCs) hold the advantages of easy availability, minimal immune rejection, and excellent immunomodulatory effects, although hUCMSCs-EVs have seldom been applied in OA. Herein, we investigated the potential immunomodulatory and anti-inflammatory effects of hUCMSCs-EVs on the treatment of OA. In our results, the treatment of hUCMSCs-EVs promoted the polarization of M2-type macrophages and the expression of anti-inflammation-related cytokines (IL-10). Notably, the supernate of M2 macrophages induced by hUCMSCs-EVs inhibited the level of inflammation-associated factors in OA chondrocytes caused by IL-1β. Further, injection of hUCMSCs-EVs in the articular lumen ameliorated progression of OA and exerted chondroprotective potential based on the OA joint model created by the surgical transection of the anterior cruciate ligament (ACLT). In addition, we found five highly enriched miRNAs in hUCMSCs-EVs, including has-miR-122-5p, has-miR-148a-3p, has-miR-486-5p, has-miR-let-7a-5p, and has-miR-100-5p by High-throughput sequencing of miRNAs, with targeted genes mainly enriched in the PI3K-Akt signaling pathway. Furthermore, we also detected the protein abundance of hUCMSCs-EVs using liquidation chromatography with tandem quadrupole mass spectrometry (LC–MS/MS) analysis. Thus, our study indicates that hUCMSCs-EVs can alleviate cartilage degradation during the OA progression, mechanically may through delivering key proteins and modulating the PI3K-Akt signaling pathway mediated by miRNAs to promote polarization of M2 macrophage, exhibiting potent immunomodulatory potential. The current findings suggest that hUCMSCs-EVs might serve as a new reagent for the therapy of OA.Graphical

Highlights

Osteoarthritis (OA) is a chronic osteoarthropathy distinguished by chronic progressive degeneration of the articular cartilage and inflammation of the synovial joint [1]
This study explored the therapeutic effects of Human umbilical cord mesenchymal stem cells (hUCMSCs)-extracellular vesicles (EVs) on OA based on the OA chondrocytes mediated by IL-1β in vitro and OA model induced by the surgical transection of the anterior cruciate ligament (ACLT) in vivo
We found that hUCMSCs-EVs alleviated the process of OA possibly by delivering critical proteins and miRNA like has-miR-122-5p, has-miR-148a-3p, hasmiR-486-5p, has-miR-let-7a-5p, and has-miR-100-5p to activate the PI3K-Akt signaling pathway that promotes polarization of M2 macrophage, which is implicated in the modulation of inflammation and immunoreaction

Summary

Introduction

Osteoarthritis (OA) is a chronic osteoarthropathy distinguished by chronic progressive degeneration of the articular cartilage and inflammation of the synovial joint [1]. It may elicit joint pains and dysfunctions, even severe disabilities for patients. Pharmacological treatments only temporarily control inflammation and alleviate the pain but can not prevent cartilage destruction in OA. Surgical treatment such as arthroplasty or total joint replacement surgery causes a great deal of stress on the patients with OA both physically and financially [2]. It is necessary to develop new therapeutic strategies that can reduce inflammation and promote regeneration of the degenerated cartilage

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Results

Conclusion