Research Paper Volume 12, Issue 18 pp 18436—18452

Nudt21-mediated alternative polyadenylation of HMGA2 3′-UTR impairs stemness of human tendon stem cell

Yangbai Sun1, *, , Hua Chen2, *, , Hui Ye3, , Wenqing Liang4, , Kun-kuan Lam5, , Biao Cheng6, , Yong Lu7, , Chaoyin Jiang2,8, ,

  • 1 Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
  • 2 Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
  • 3 Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
  • 4 Department of Orthopaedics, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing 312000, Zhejiang, China
  • 5 Department of Orthopaedic Surgery and Sports Medicine, University Hospital of Macau University of Science and Technology, Macau 999078, China
  • 6 Department of Orthopedics, Shanghai Tenth People’s Hospital, Tongji University, School of Medicine, Shanghai 200072, China
  • 7 Department of Radiology, Rui Jin Hospital, Lu Wan Branch, School of Medicine, Shanghai Jiaotong University, Shanghai 200020, China
  • 8 Department of Orthopedic Surgery, Haikou Orthopedic and Diabetes Hospital of Shanghai Sixth People's Hospital, Hainan 570300, China
* Equal contribution and Co-first authors

Received: January 16, 2020       Accepted: July 6, 2020       Published: September 26, 2020
How to Cite

Copyright: © 2020 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Tendon-derived stem cells (TSCs) play a primary role in tendon physiology, pathology, as well as tendon repair and regeneration after injury. TSCs are often exposed to mechanical loading-related cellular stresses such as oxidative stress, resulting in loss of stemness and multipotent differentiation potential. Cytoprotective autophagy has previously been identified as an important mechanism to protect human TSCs (hTSCs) from oxidative stress induced impairments. In this study, we found that high-mobility AT-hook 2 (HMGA2) overexpression protects hTSCs against H2O2-induced loss of stemness through autophagy activation. Evidentially, H2O2 treatment increases the expression of Nudt21, a protein critical to polyadenylation site selection in alternative polyadenylation (APA) of mRNA transcripts. This leads to increased cleavage and polyadenylation of HMGA2 3′-UTR at the distal site, resulting in increased HMGA2 silencing by the microRNA let-7 and reduced HMGA2 expression. In conclusion, Nudt21-regulated APA of HMGA2 3′-UTR and subsequent HMGA2 downregulation mediates oxidative stress induced hTSC impairments.


TSCs: tendon-derived stem cells; hTSCs: human TSCs; HMGA2: high-mobility group AT-hook 2; APA: alternative polyadenylation; 3′-UTR: 3′-untranslated region; miRNA: microRNA; CPSF5: cleavage and polyadenylation specificity factor subunit 5; CFIm: cleavage factor Im; 3-MA: 3-methyladenine; CCK-8: counting Kit-8; β-gal: β-galactosidase; rTSCs: rat TSCs; DRAM: damage-regulated autophagy modulator; shRNAs: short hairpin RNAs; qRT-PCR: quantitative real-time PCR; SD: standard deviation.