ASIC1 and ASIC3 mediate cellular senescence of human nucleus pulposus mesenchymal stem cells during intervertebral disc degeneration.
Jingyu Ding, Renjie Zhang, Huimin Li, Qiang Ji, Xiaomin Cheng, Rick Francis Thorne, Hubert Hondermarck, Xiaoying Liu, Cailiang Shen
Author Information
Jingyu Ding: Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, China.
Renjie Zhang: Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, China.
Huimin Li: Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, China.
Qiang Ji: School of Life Sciences, Anhui Medical University, Hefei 230032, Anhui, China.
Xiaomin Cheng: School of Life Sciences, Anhui Medical University, Hefei 230032, Anhui, China.
Rick Francis Thorne: Translational 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.
Hubert Hondermarck: School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia.
Xiaoying Liu: School of Life Sciences, Anhui Medical University, Hefei 230032, Anhui, China.
Cailiang Shen: Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei 230032, Anhui, China.
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 system that can be used to evaluate other IVDD therapies.
