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Research Paper|Volume 13, Issue 7|pp 10703—10723

ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration

Jingyu Ding1,2, Renjie Zhang1, Huimin Li1, Qiang Ji2, Xiaomin Cheng2, Rick Francis Thorne3, Hubert Hondermarck4, Xiaoying Liu2,3, Cailiang Shen1
  • 1Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, China
  • 2School of Life Sciences, Anhui Medical University, Hefei 230032, Anhui, China
  • 3Translational Research Institute of Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Molecular Pathology Centre, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450053, Henan, China
  • 4School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia
* Equal contribution
Received: October 10, 2020Accepted: February 16, 2021Published: April 6, 2021
https://doi.org/10.18632/aging.202850

Copyright: © 2021 Ding 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.

Abstract

Stem cell approaches have become an attractive therapeutic option for intervertebral disc degeneration (IVDD). Nucleus pulposus mesenchymal stem cells (NP-MSCs) participate in the regeneration and homeostasis of the intervertebral disc (IVD), but the molecular mechanisms governing these processes remain to be elucidated. Acid-sensing ion channels (ASICs) which act as key receptors for extracellular protons in central and peripheral neurons, have been implicated in IVDD where degeneration is associated with reduced microenvironmental pH. Here we show that ASIC1 and ASIC3, but not ASIC2 and ASIC4 are upregulated in human IVDs according to the degree of clinical degeneration. Subjecting IVD-derived NP-MSCs to pH 6.6 culture conditions to mimic pathological IVD changes resulted in decreased cell proliferation that was associated with cell cycle arrest and induction of senescence. Key molecular changes observed were increased expression of p53, p21, p27, p16 and Rb1. Instructively, premature senescence in NP-MSCs could be largely alleviated using ASIC inhibitors, suggesting both ASIC1 and ASIC3 act decisively upstream to activate senescence programming pathways including p53-p21/p27 and p16-Rb1 signaling. These results highlight the potential of ASIC inhibitors as a therapeutic approach for IVDD and broadly define an in vitro system that can be used to evaluate other IVDD therapies.