Chen Y, Hu X, Jia XT, Gao RZ, Hou QS, Zhou SG. WTAP-mediated N6-methyladenosine modification of circ_PVT1 promotes proliferation and tenogenic differentiation of tendon stem/progenitor cells. World J Stem Cells 2026; 18(4): 115218 [DOI: 10.4252/wjsc.v18.i4.115218]
Corresponding Author of This Article
Shi-Guo Zhou, MD, Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134 East Street, Fuzhou 350001, Fujian Province, China. 9201551033@fjmu.edu.cn
Research Domain of This Article
Orthopedics
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
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: http://creativecommons.org/licenses/by-nc/4.0/
Yu Chen, Xu Hu, Ren-Zhi Gao, Shi-Guo Zhou, Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, Fuzhou 350001, Fujian Province, China
Xiao-Tian Jia, Quan-Shan Hou, Department of Orthopedics, Changji Hui Autonomous Prefecture People’s Hospital, Changji Hui Autonomous Prefecture 831100, Xinjiang Uyghur Autonomous Region, China
Co-first authors: Yu Chen and Xu Hu.
Co-corresponding authors: Quan-Shan Hou and Shi-Guo Zhou.
Author contributions: Chen Y and Hu X contributed equally to this manuscript and are co-first authors. Chen Y, Hu X, and Zhou SG designed and supervised the study; Chen Y, Jia XT, and Hou QS conducted the experiments and drafted the manuscript; Chen Y, Gao RZ, and Hou QS collected and analyzed the data; Hu X and Jia XT contributed the methodology; Chen Y, Hu X, and Zhou SG operated the software and edited the manuscript; Hou QS and Zhou SG contributed equally to this manuscript and are co-corresponding authors. All authors reviewed the manuscript.
Supported by Natural Science Foundation of Fujian Province, No. 2024J011037.
Institutional animal care and use committee statement: The protocol for the animal experiment was reviewed and approved by the Ethics Committee of Fuzhou University Affiliated Provincial Hospital for experimental animal welfare, approval No. IACUC-FPH-SL-20240321[0219].
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Data will be made available upon reasonable request.
Corresponding author: Shi-Guo Zhou, MD, Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fuzhou University Affiliated Provincial Hospital, No. 134 East Street, Fuzhou 350001, Fujian Province, China. 9201551033@fjmu.edu.cn
Received: October 31, 2025 Revised: December 14, 2025 Accepted: February 24, 2026 Published online: April 26, 2026 Processing time: 170 Days and 23.9 Hours
Abstract
BACKGROUND
Tendon stem/progenitor cells (TSPCs) are a novel type of stem cell. TSPCs share common characteristics with stem cells, including their proliferation, pluripotency, and self-renewal abilities. Circular RNA plasmacytoma variant translocation 1 (circ_PVT1) has been reported to inhibit senescence in TSPCs. However, the mechanism by which circ_PVT1 regulates the proliferation and differentiation of TSPCs remains unclear.
AIM
To explore how circ_PVT1 regulates the proliferation and differentiation of TSPCs.
METHODS
Mouse TSPCs were isolated from the Achilles tendon of 12 male C57Bl/6 mice at postnatal day 30, and 5 ng/mL of transforming growth factor (TGF)-β1 was used to induce the tenogenic differentiation in TSPCs. Picro-Sirius red staining was used to detect the collagen expression of TSPCs. A Cell Counting Kit-8, Transwell assays, and flow cytometry were used to assess the proliferation, migration, and apoptosis of TSPCs. Biochemical kits were used to determine the levels of reactive oxygen species, malondialdehyde, glutathione, superoxide dismutase, and ATP. Then, N6-methyladenosine (m6A) dot blot and methylated RNA immunoprecipitation polymerase chain reaction (RIP-PCR) were used to examine the m6A levels. Moreover, RNA pulldown and RIP-PCR were performed to analyze the interaction between WTAP and circ_PVT1.
RESULTS
TGF-β1 treatment induced tenogenic differentiation of TSPCs. Circ_PVT1 knockdown reversed the increase of tendon-specific protein, cell proliferation, and migration that was induced by TGF-β1 treatment. In addition, circ_PVT1 inhibition promoted oxidative stress and mitochondrial damage in the TGF-β1-induced TSPCs. The m6A modification level of circ_PVT1 was upregulated in the TGF-β1-induced TSPCs. Furthermore, RNA pulldown and RIP-PCR showed that circ_PVT1 interacted with WTAP in TSPCs, and the WTAP-mediated m6A modification of circ_PVT1 regulated the differentiation of TSPCs.
CONCLUSION
WTAP-mediated m6A modification of circ_PVT1 promotes the proliferation and tenogenic differentiation of TSPCs, thereby indicating a promising therapeutic strategy for tendon repair.
Core Tip: Tendon stem/progenitor cells share common characteristics with stem cells, such as proliferation, pluripotency, and self-renewal ability. Under suitable conditions, they can differentiate into tendon cells and play a crucial role in maintaining the stability of tendons and in repair after injury. We found that circular RNA plasmacytoma variant translocation 1 deficiency could inhibit tenogenic differentiation. In addition, WTAP-mediated N6-methyladenosine modification of circular RNA plasmacytoma variant translocation 1 promotes the proliferation and tenogenic differentiation of tendon stem/progenitor cells. These results suggest a promising therapeutic strategy for tendon diseases.
