Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Feb 26, 2024; 16(2): 191-206
Published online Feb 26, 2024. doi: 10.4252/wjsc.v16.i2.191
Extracellular vesicles derived from mesenchymal stem cells mediate extracellular matrix remodeling in osteoarthritis through the transport of microRNA-29a
Fan Yang, Wan-Qi Xiong, Chen-Zhi Li, Ming-Jian Wu, Xiu-Zhi Zhang, Chun-Xiao Ran, Zhen-Hao Li, Yan Cui, Bao-Yi Liu, De-Wei Zhao
Fan Yang, Wan-Qi Xiong, Chen-Zhi Li, Ming-Jian Wu, Xiu-Zhi Zhang, Chun-Xiao Ran, Zhen-Hao Li, Yan Cui, Bao-Yi Liu, De-Wei Zhao, Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116001, Liaoning Province, China
Author contributions: Liu BY and Zhao DW was the guarantor and designed the study; Yang F and Xiong WQ participated in the acquisition, analysis, and interpretation of the data, and drafted the initial manuscript; Li CZ, Wu MJ, Zhang XZ, Ran CX, Li ZH, and Cui Y revised the article critically for important intellectual content.
Supported by Project of the National Natural Science Foundation of China, No. 82172398; Key Research Project of the Department of Education of Liaoning Province, No. LJKZZ20220148; Dalian Medical Science Research Project, No. 2111038; and Dalian Dengfeng Plan Medical Key Specialty Construction Project (2021), No. 243.
Institutional animal care and use committee statement: All animal studies were approved by the Animal Welfare and Ethics Committee of the Affiliated Zhongshan Hospital of Dalian University (No. 2022011010).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Bao-Yi Liu, PhD, Chief, Professor, Surgeon, Teacher, Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, No. 6 Jiefang Street, Zhongshan District, Dalian 116001, Liaoning Province, China. liubaoyi-513@163.com
Received: October 26, 2023
Peer-review started: October 26, 2023
First decision: November 9, 2023
Revised: November 18, 2023
Accepted: January 30, 2024
Article in press: January 30, 2024
Published online: February 26, 2024
Processing time: 123 Days and 1.2 Hours
Abstract
BACKGROUND

Knee osteoarthritis (KOA) is a common orthopedic condition with an uncertain etiology, possibly involving genetics and biomechanics. Factors like changes in chondrocyte microenvironment, oxidative stress, inflammation, and immune responses affect KOA development. Early-stage treatment options primarily target symptom relief. Mesenchymal stem cells (MSCs) show promise for treatment, despite challenges. Recent research highlights microRNAs (miRNAs) within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA progression. This suggests exosomes (Exos) as a promising avenue for future treatment. While these findings emphasize the need for effective KOA progression management, further safety and efficacy validation for Exos is essential.

AIM

To explore miR-29a’s role in KOA, we’ll create miR-29a-loaded vesicles, testing for early treatment in rat models.

METHODS

Extraction of bone marrow MSC-derived extracellular vesicles, preparation of engineered vesicles loaded with miR-29a using ultrasonication, and identification using quantitative reverse transcription polymerase chain reaction; after establishing a rat model of KOA, rats were randomly divided into three groups: Blank control group injected with saline, normal extracellular vesicle group injected with normal extracellular vesicle suspension, and engineered extracellular vesicle group injected with engineered extracellular vesicle suspension. The three groups were subjected to general behavioral observation analysis, imaging evaluation, gross histological observation evaluation, histological detection, and immunohistochemical detection to compare and evaluate the progress of various forms of arthritis.

RESULTS

General behavioral observation results showed that the extracellular vesicle group and engineered extracellular vesicle group had better performance in all four indicators of pain, gait, joint mobility, and swelling compared to the blank control group. Additionally, the engineered extracellular vesicle group had better pain relief at 4 wk and better knee joint mobility at 8 wk compared to the normal extracellular vesicle group. Imaging examination results showed that the blank control group had the fastest progression of arthritis, the normal extracellular vesicle group had a relatively slower progression, and the engineered extracellular vesicle group had the slowest progression. Gross histological observation results showed that the blank control group had the most obvious signs of arthritis, the normal extracellular vesicle group showed signs of arthritis, and the engineered extracellular vesicle group showed no significant signs of arthritis. Using the Pelletier gross score evaluation, the engineered extracellular vesicle group had the slowest progression of arthritis. Results from two types of staining showed that the articular cartilage of rats in the normal extracellular vesicle and engineered extracellular vesicle groups was significantly better than that of the blank control group, and the engineered extracellular vesicle group had the best cartilage cell and joint surface condition. Immunohistochemical detection of type II collagen and proteoglycan showed that the extracellular matrix of cartilage cells in the normal extracellular vesicle and engineered extracellular vesicle groups was better than that of the blank control group. Compared to the normal extracellular vesicle group, the engineered extracellular vesicle group had a better regulatory effect on the extracellular matrix of cartilage cells.

CONCLUSION

Engineered Exos loaded with miR-29a can exert anti-inflammatory effects and maintain extracellular matrix stability, thereby protecting articular cartilage, and slowing the progression of KOA.

Keywords: Exosomes, Osteoarthritis, Mesenchymal stem cells, MicroRNA-29a, Intra-articular injection

Core Tip: Knee osteoarthritis (KOA) is a common orthopedic condition with an uncertain etiology, involving genetics and biomechanics. Factors like changes in chondrocyte microenvironment, oxidative stress, inflammation, and immune responses affect KOA. Mesenchymal stem cells (MSCs) show promise in treatment. Recent research highlights microRNAs (miRNAs) within MSC-released extracellular vesicles that can potentially promote cartilage regeneration and hinder KOA. Engineered exosomes (Exos) loaded with miR-29a were used in a rat study for early-stage KOA treatment, showing superior pain reduction and joint improvement compared to standard Exos. These findings suggest that miR-29a-loaded Exos could be a novel therapeutic approach for early-stage KOA management.