Serglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration

Chen, Fan; Lei, Linchuan; Chen, Shunlun; Zhao, Zhuoyang; Huang, Yuming; Jiang, Guowei; Guo, Xingyu; Li, Zemin; Zheng, Zhaomin; Wang, Jianru

doi:10.1038/s41467-023-44313-9

Cited by 3 publications

(1 citation statement)

References 53 publications

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“…It offers insights into physiological and pathological processes and has been increasingly applied in IVD research. Several studies have identified novel phenotypic biomarkers of NP cells, significantly enhancing our understanding of NP cell biology and development ( Fernandes et al, 2020 ; Ling et al, 2021 ; Panebianco et al, 2021 ; Zhang et al, 2021 ; Cherif et al, 2022 ; Han et al, 2022 ; RNA, 2022 ; Guo et al, 2023a ; Chen et al, 2024 ). However, the heterogeneity of IVDD among young and elderly individuals remains to be fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics

Liu,

Ren,

Zhang

et al. 2024

Front. Cell Dev. Biol.

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Introduction: Intervertebral disc degeneration often occurs in the elderly population, but in recent years, there has been an increasing incidence of disc degeneration in younger individuals, primarily with mild degeneration.Methods: In order to explore the underlying mechanisms of disc degeneration in both young and aging individuals, we collected four types of nucleus pulposus (NP) single-cell sequencing samples for analysis based on Pfirrmann grading: normal-young (NY) (Grade I), normal-old (NO) (Grade I), mild degenerative-young (MY) (Grade II-III), and mild degenerative-old (MO) (Grade II-III).Results: We found that most NP cells in NO and MY samples exhibited oxidative stress, which may be important pathogenic factors in NO and MY groups. On the other hand, NP cells in MO group exhibited endoplasmic reticulum stress. In terms of inflammation, myeloid cells were mainly present in the degenerative group, with the MY group showing a stronger immune response compared to the MO group. Interestingly, dendritic cells in the myeloid lineage played a critical role in the process of mild degeneration.Discussion: Our study investigated the molecular mechanisms of intervertebral disc degeneration from an age perspective, providing insights for improving treatment strategies for patients with disc degeneration at different age groups.

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Section: Introductionmentioning

confidence: 99%

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics

Liu,

Ren,

Zhang

et al. 2024

Front. Cell Dev. Biol.

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TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions

Gansau,

Grossi,

Rodriguez

et al. 2024

Preprint

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Intervertebral disc (IVD) degeneration (IVDD) progresses to herniation and back pain due to the poor IVD healing capacities. However, factors contributing to inferior IVD repair remain to be elucidated. Here we identify distinct roles of TNFα-receptors (TNFRs) in IVD cell responses to back pain conditions as key factors in poor IVD healing responses. IVDD tissue of back pain subjects with herniation secreted a complex array of pro-inflammatory cytokines and chemokines (including IL-6, IL-10, CCL2 and CCL5) collected as IVDD conditioned media (IVDD-CM). Single-cell RNA-sequencing (scRNA-seq) of human IVDD tissues revealed these cytokines were dominantly expressed by a small macrophage-population with surprisingly low expression by native IVD cells. Human annulus fibrosus (hAF) cells from surgical tissue had reduced metabolic rates and underwent senescence in IVDD-CM, whereas Basal media restored mitotic potential. Inhibiting the TNFR1 pathway in hAF cells under IVDD-CM challenge enhanced proliferation and induced pro-inflammatory responses with extensive cytokines and chemokines produced. Surprisingly, modulating the pro-reparative TNFR2 using blocking antibodies or using Atsttrin as TNFR2 activator had no effect on hAF cell transcriptome. We discovered TNFR2 was lacking on hIVD cell membranes using immunostaining and scRNA-seq on human autopsy samples and back pain tissue. The absence of TNFR2 on hIVD cells is a new finding revealing these cells are inherently limited in their repair response to inflammatory challenges. Results point to a TNFR-specific strategy for IVD repair involving TNFR1 inhibition to restore IVD cell metabolism and express chemokines to recruit TNFR2-expressing cells capable of a more robust repair response.

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The landscape of immune cell infiltration and potential biomarkers in intervertebral disc degeneration

Wang,

Hu,

Tian

et al. 2024

Preprint

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Background Immune cell infiltration has been found to be strongly associated with the occurrence and progression of intervertebral disc degeneration (IDD), and intervertebral discs (IVDs) are immune-privileged organs. This research aimed to identify novel targets for therapeutic intervention and investigate significant physiological and cellular mechanisms involved in the immune infiltration processes of IDD. Results CIBERSORT deconvolution analysis revealed that the levels of follicular helper T cells and M2 macrophages were significantly increased during IDD, while the levels of resting mast cells were significantly decreased. WGCNA revealed that the blue module was associated with macrophage infiltration (positive correlation 0.87, P < 0.001), of which genes, including VAMP8, TLR4, JUN, PLA2G4A, NMI, RORA, IFNGR1, IFNGR2, NINJ1, TNIP1, and CD81, were mainly enriched in macrophage activation, myeloid leukocyte activation and the Toll-like receptor 4 signaling pathway. The proportion of leukocytes in the IVD was greatest on the 14th day after puncture. Single-cell sequencing revealed the division of degenerative IVD cells into seven major cell types, annulus fibrosus cells, smooth muscle cells, fibroblasts, macrophages, monocytes, vascular endothelial cells, and NP cells, in which Jun, Cd81, Rora, Vamp8, Ninj1, and Tnip1 were strongly expressed, western blotting results in normal and degenerated nucleus pulposus cells (NNP and DNP) showed that the expression of VAMP8 and c-Jun increased after 24 hours of stimulation with 50 ng/ml TNF-α. The immunohistochemical results showed an increase in VAMP8 and c-Jun levels in the IVD of rats on the 14th day after acupuncture. Conclusion The 14th day after acupuncture in the IVD of rats is a crucial time point for the infiltration of immune cells. This work is the first to reveal that VAMP8 and c-Jun are linked to the infiltration of macrophages in IDD. Elevated expression of VAMP8 and c-Jun was confirmed in both DNP and punctured rat IVDs.

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Serglycin secreted by late-stage nucleus pulposus cells is a biomarker of intervertebral disc degeneration

Cited by 3 publications

References 53 publications

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics

Investigating the characteristics of mild intervertebral disc degeneration at various age stages using single-cell genomics

TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions

The landscape of immune cell infiltration and potential biomarkers in intervertebral disc degeneration

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