Comparison of Curative Effect of Human Umbilical Cord-Derived Mesenchymal Stem Cells and Their Small Extracellular Vesicles in Treating Osteoarthritis

Shijie Tang; Penghong Chen; Haoruo Zhang; Haiyan Weng; Zhuoqun Fang; Caixiang Chen; Guohao Peng; Hangqi Gao; Kailun Hu; Jinghua Chen; Liangwan Chen; Xiaosong Chen

doi:10.2147/IJN.S336062

Comparison of Curative Effect of Human Umbilical Cord-Derived Mesenchymal Stem Cells and Their Small Extracellular Vesicles in Treating Osteoarthritis

Int J Nanomedicine. 2021 Dec 16:16:8185-8202. doi: 10.2147/IJN.S336062. eCollection 2021.

Authors

Shijie Tang^#^{1

2

3

4}, Penghong Chen^#^{1

2

3

4}, Haoruo Zhang^{1

2

3

4}, Haiyan Weng^{1

2

3

4}, Zhuoqun Fang^{1

2

3

4}, Caixiang Chen^{1

2

3

4}, Guohao Peng^{1

2

3

4}, Hangqi Gao^{1

2

3

4}, Kailun Hu^{1

2

3

4}, Jinghua Chen⁵, Liangwan Chen^{3

6}, Xiaosong Chen^{1

2

3}

Affiliations

¹ Department of Plastic Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China.
² Department of Plastic Surgery and Regenerative Medicine Institute, Fujian Medical University, Fuzhou, 350001, People's Republic of China.
³ Engineering Research Center of Tissue and Organ Regeneration, Fujian Province University, Fuzhou, 350001, People's Republic of China.
⁴ Oncology Institution, Fujian Medical University, Fuzhou, 350004, People's Republic of China.
⁵ Department of Pharmaceutical Analysis, the School of Pharmacy, Fujian Medical University, Fuzhou, 350100, People's Republic of China.
⁶ Department of Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, People's Republic of China.

^# Contributed equally.

Abstract

Introduction: Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and their small extracellular vesicles (hUC-MSC-sEVs) have shown attractive prospects applying in regenerative medicine. This study aimed to compare the therapeutic effects of two agents on osteoarthritis (OA) and investigate underlying mechanism using proteomics.

Methods: In vitro, the proliferation and migration abilities of chondrocytes treated with hUC-MSCs or hUC-MSC-sEVs were detected by Cell Counting Kit-8 assay and scratch wound assay. In vivo, hUC-MSCs (a single dose of 5 × 10⁵) or hUC-MSC-sEVs (30 μg/time) were injected into the knee joints of anterior cruciate ligament transection-induced OA model. Hematoxylin and eosin, Safranin O/Fast Green staining were used to observe cartilage degeneration. The levels of cartilage matrix metabolic molecules (Collagen II, MMP13 and ADAMTS5) and macrophage polarization markers (CD14, IL-1β, IL-10 and CD206) were assessed by immunohistochemistry. Finally, proteomics analysis was performed to characterize the proteinaceous contents of two agents.

Results: In vitro data showed that hUC-MSC-sEVs were taken up by chondrocytes. A total of 15 μg/mL of sEVs show the greatest proliferative and migratory capacities among all groups. In the animal study, hUC-MSCs and hUC-MSC-sEVs alleviated cartilage damage. This effect was mediated via maintaining cartilage homeostasis, as was confirmed by upregulation of the COL II and downregulation of the MMP13 and ADAMTS5. Moreover, the M1 macrophage markers (CD14) were significantly reduced, while the M2 macrophage markers (CD206 and IL-10) were increased in the hUC-MSCs and hUC-MSC-sEVs relative to the untreated group. Mechanistically, we found that many proteins connected to cartilage repair were more abundant in sEVs. Notably, compared to hUC-MSCs, the upregulated proteins in sEVs were mostly involved in the regulation of immune effector process, extracellular matrix organization, PI3K-AKT signaling pathways, and Rap1 signaling pathway.

Conclusion: Our study indicated that hUC-MSC-sEVs protect cartilage from damage and many cartilage repair-related proteins are probably involved in the restoration process. These data suggest the promising potential of hUC-MSC-sEVs as a therapeutic agent for OA.

Keywords: cell-free therapy; human umbilical cord-derived mesenchymal stem cells; osteoarthritis; proteomics; small extracellular vesicles.

MeSH terms

Animals
Extracellular Vesicles*
Humans
Mesenchymal Stem Cell Transplantation*
Mesenchymal Stem Cells*
Osteoarthritis* / therapy
Phosphatidylinositol 3-Kinases
Umbilical Cord

Grants and funding

This study was financed by National Natural Science Foundation of China (grant No. 81971855), Joint funding Project of Science and Technology Innovation in Fujian Province (grant No. 2017Y9101), Special Financial Funds of Fujian Province (grant Nos. 2018B054 and 2020CZ016) and Industrial Technology Joint Innovation Project of Fujian Provincial Development and Reform Commission (grant No. 2011601).