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

Apr 7, 2021Aging

How ASIC1 and ASIC3 proteins contribute to aging of spine stem cells during disc degeneration

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

ASIC1 and ASIC3 are upregulated in human intervertebral discs with increasing clinical degeneration.

Nucleus pulposus mesenchymal stem cells (NP-MSCs) show decreased proliferation under acidic conditions mimicking intervertebral disc degeneration.
Cell cycle arrest and induction of senescence are observed in NP-MSCs when cultured at pH 6.6.
Increased expression of key regulatory proteins p53, p21, p27, p16, and Rb1 is associated with the senescence of NP-MSCs.
Inhibition of ASIC1 and ASIC3 largely alleviates premature senescence in NP-MSCs.
These findings suggest ASIC1 and ASIC3 play significant roles in activating pathways that lead to cell senescence.

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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 ansystem that can be used to evaluate other IVDD therapies. in vitro

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

Abstract

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