Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2019; 11(12): 1115-1129
Published online Dec 26, 2019. doi: 10.4252/wjsc.v11.i12.1115
Anti-osteoarthritis effect of a combination treatment with human adipose tissue-derived mesenchymal stem cells and thrombospondin 2 in rabbits
Kyungha Shin, Yeseul Cha, Young-Hwan Ban, Da Woom Seo, Ehn-Kyoung Choi, Dongsun Park, Sung Keun Kang, Jeong Chan Ra, Yun-Bae Kim
Kyungha Shin, Yeseul Cha, Young-Hwan Ban, Da Woom Seo, Ehn-Kyoung Choi, Yun-Bae Kim, College of Veterinary Medicine, Chungbuk National University, Cheongju 28644, Chungbuk, South Korea
Dongsun Park, Department of Biology Education, Korea National University of Education, Cheongju 28173, Chungbuk, South Korea
Sung Keun Kang, Jeong Chan Ra, Biostar Stem Cell Research Institute, R-BIO Co., Ltd., Seoul 07238, South Korea
Author contributions: Shin K, Cha Y, and Ban YH performed animal experiments and assembled histological samples; Seo DW performed the cell differentiation study; Choi EK and Park D collected and analyzed the data; Kang SK prepared and characterized the stem cells; Ra CJ and Kim YB designed and interpreted the study, and wrote the manuscript.
Supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT to Y.B.K., No. 2017R1A2A2A05069417
Institutional review board statement: All human tissues were obtained with approval of the Institutional Review Board of K-Stem Cell (Seoul, Korea).
Institutional animal care and use committee statement: All protocols and procedures of animal experiments complied with the Institutional Animal Care and Use Committee of Laboratory Animal Research Center at Chungbuk National University (Chungbuk, Korea).
Conflict-of-interest statement: The author has no conflict of interest to declare.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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:
Corresponding author: Yun-Bae Kim, DVM, PhD, Professor, College of Veterinary Medicine, Chungbuk National University, 1 Chungdaero (Gaesin-dong), Cheongju 28644, Chungbuk, South Korea.
Telephone: +82-43-2613358
Received: February 27, 2019
Peer-review started: February 27, 2019
First decision: August 1, 2019
Revised: October 14, 2019
Accepted: November 4, 2019
Article in press: November 4, 2019
Published online: December 26, 2019

Osteoarthritis (OA), a chronic age-related disease characterized by the slowly progressive destruction of articular cartilage, is one of the leading causes of disability. As a new strategy for treatment of OA, mesenchymal stem cells (MSCs) have the potential for articular cartilage regeneration. Meanwhile, thrombospondin 2 (TSP2) promotes the chondrogenic differentiation of MSCs.


To investigate whether TSP2 induces chondrogenic differentiation of human adipose-derived MSCs (hADMSCs) and potentiates the therapeutic effects of hADMSCs in OA rabbits.


We investigated the chondrogenic potential of TSP2 in hADMSCs by analyzing the expression of chondrogenic markers as well as NOTCH signaling genes in normal and TSP2 small interfering RNA (siRNA)-treated stem cells. Anterior cruciate ligament transection surgery was performed in male New Zealand white rabbits, and 8 wk later, hADMSCs (1.7 × 106 or 1.7 × 107 cells) were injected into the injured knees alone or in combination with intra-articular injection of TSP2 (100 ng/knee) at 2-d intervals. OA progression was monitored by gross, radiological, and histological examinations.


In hADMSC culture, treatment with TSP2 increased the expression of chondrogenic markers (SOX9 and collagen II) as well as NOTCH signaling genes (JAGGED1 and NOTCH3), which were inhibited by TSP2 siRNA treatment. In vivo, OA rabbits treated with hADMSCs or TSP2 alone exhibited lower degree of cartilage degeneration, osteophyte formation, and extracellular matrix loss 8 wk after cell transplantation. Notably, such cartilage damage was further alleviated by the combination of hADMSCs and TSP2. In addition, synovial inflammatory cytokines, especially tumor-necrosis factor-α, markedly decreased following the combination treatment.


The results indicate that TSP2 enhances chondrogenic differentiation of hADMSCs via JAGGED1/NOTCH3 signaling, and that combination therapy with hADMSCs and TSP2 exerts synergistic effects in the cartilage regeneration of OA joints.

Keywords: Osteoarthritis, Anterior cruciate ligament transection, Human adipose tissue-derived mesenchymal stem cell, Thrombospondin 2, Notch signaling, Cartilage regeneration

Core tip: We demonstrated the role of thrombospondin 2 (referred to as TSP2) in the chondrogenic differentiation of human adipose-derived mesenchymal stem cells in vitro and in osteoarthritis therapy with the cells in vivo. TSP2 induced chondrogenic differentiation via JAGGED1/NOTCH signaling, and potentiated the cartilage-restoring efficacy of human adipose-derived mesenchymal stem cells.