Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Nov 26, 2022; 14(11): 798-814
Published online Nov 26, 2022. doi: 10.4252/wjsc.v14.i11.798
Tumor necrosis factor-α inhibition restores matrix formation by human adipose-derived stem cells in the late stage of chondrogenic differentiation
Jiang-Tao Wan, Xian-Shuai Qiu, Zhuo-Hang Fu, Yong-Can Huang, Shao-Xiong Min
Jiang-Tao Wan, Zhuo-Hang Fu, Yong-Can Huang, Shao-Xiong Min, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
Jiang-Tao Wan, Zhuo-Hang Fu, Yong-Can Huang, Institute of Orthopedics, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen 518036, Guangdong Province, China
Xian-Shuai Qiu, Shao-Xiong Min, Department of Spine Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China
Author contributions: Min SX and Wan JT conceived and designed the experiments; Wan JT, Qiu XS, and Fu ZH performed the experiments; Wan JT and Qiu XS analyzed the data; Wan JT and Huang YC composed the manuscript.
Supported by the Natural Science Foundation of Guangdong Province, China, No. 2017A030313564; and Shenzhen High-level Hospital Construction Fund to Peking University Shenzhen Hospital.
Institutional review board statement: This study was approved by the Ethics Committee of Peking University Shenzhen Hospital (No. 2022-076).
Conflict-of-interest statement: The author has no conflict of interest to declare.
Data sharing statement: No additional data are available.
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: Shao-Xiong Min, PhD, Chief Physician, Department of Spine Surgery, Peking University Shenzhen Hospital, No. 1120 Lianhua Road, Futian District, Shenzhen 518036, Guangdong Province, China. msxbear24@163.com
Received: July 20, 2022
Peer-review started: July 20, 2022
First decision: August 8, 2022
Revised: October 5, 2022
Accepted: November 22, 2022
Article in press: November 22, 2022
Published online: November 26, 2022
Abstract
BACKGROUND

Cartilage tissue engineering is a promising strategy for treating cartilage damage. Matrix formation by adipose-derived stem cells (ADSCs), which are one type of seed cell used for cartilage tissue engineering, decreases in the late stage of induced chondrogenic differentiation in vitro, which seriously limits research on ADSCs and their application.

AIM

To improve the chondrogenic differentiation efficiency of ADSCs in vitro, and optimize the existing chondrogenic induction protocol.

METHODS

Tumor necrosis factor-alpha (TNF-α) inhibitor was added to chondrogenic culture medium, and then Western blotting, enzyme linked immunosorbent assay, immunofluorescence and toluidine blue staining were used to detect the cartilage matrix secretion and the expression of key proteins of nuclear factor kappa-B (NF-κB) signaling pathway.

RESULTS

In this study, we found that the levels of TNF-α and matrix metalloproteinase 3 were increased during the chondrogenic differentiation of ADSCs. TNF-α then bound to its receptor and activated the NF-κB pathway, leading to a decrease in cartilage matrix synthesis and secretion. Blocking TNF-α with its inhibitors etanercept (1 μg/mL) or infliximab (10 μg/mL) significantly restored matrix formation.

CONCLUSION

Therefore, this study developed a combination of ADSC therapy and targeted anti-inflammatory drugs to optimize the chondrogenesis of ADSCs, and this approach could be very beneficial for translating ADSC-based approaches to treat cartilage damage.

Keywords: Adipose-derived mesenchymal stem cells, Human adipose-derived mesenchymal stem cells, Chondrogenic differentiation, Tumor necrosis factor-alpha, Etanercept, Infliximab, Nuclear factor kappa-B

Core Tip: Adipose stem cells are important seed cells that are used in cartilage tissue engineering. However, at present, cartilage matrix secretion by adipose-derived stem cells (ADSCs) inevitably decreases during the late stage of induced chondrogenic differentiation in vitro, which seriously limits the further application of ADSCs. Our team found that the level of inflammation in the culture system, mainly the levels of tumor necrosis factor-alpha (TNF-α) and matrix metalloproteinase 3, continuously increased during the chondrogenic differentiation of ADSCs. To address this issue, our team added etanercept or infliximab, which are targeted inhibitors of TNF-α, to the chondrogenic differentiation induction medium and successfully restored matrix formation by human ADSCs in the late stage of chondrogenic differentiation. Further studies found that these effects were achieved by reducing NF-κB pathway activation.