Single Impact Injury of Vertebral Endplates Without Structural Disruption, Initiates Disc Degeneration Through Piezo1 Mediated Inflammation and Metabolism Dysfunction

Sun, Zhengang; Zheng, Xianxu; Li, Songbo; Zeng, Baozhu; Yang, Jiaming; Ling, Zemin; Liu, Xizhe; Wei, Fuxin

doi:10.1097/brs.0000000000004203

Cited by 18 publications

(22 citation statements)

References 41 publications

(78 reference statements)

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“…Consistent with previous studies, matrix metalloproteinase-3 (MMP3) was also found to be highly expressed in the inflammatory response NPC cluster (IR NPC), which accounted for a highly proportion of NP cells in the late stage of IDD. This is also consistent with our previous study that has demonstrated that inflammation was one of the main contributors to IDD ( Molinos et al, 2015 ; Wei et al, 2015 ; Wei et al, 2019 ; Sun et al, 2021 ). Further analysis showed that the gene thioredoxin-interacting protein (TXNIP), early growth response 1 (ERG1), and fibroblast growth factor 1 (FGF1) were also highly expressed in this cluster.…”

Section: Discussionsupporting

confidence: 94%

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Ling

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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Intervertebral disc degeneration (IDD) has been considered as the primary pathological mechanism that underlies low back pain. Understanding the molecular mechanisms underlying human IDD is imperative for making strategies to treat IDD-related diseases. Herein, we report the molecular programs, lineage progression patterns, and paths of cellular communications during the progression of IDD using single-cell RNA sequencing (scRNA-seq) on nucleus pulposus (NP) cells from patients with different grades of IDD undergoing discectomy. New subtypes of cells and cell-type-specific gene signatures of the metabolic homeostatic NP cells (Met NPC), adhesive NP cells (Adh NPC), inflammatory response NP cells (IR NPC), endoplasmic reticulum stress NP cells (ERS NPC), fibrocartilaginous NP cells (Fc NPC), and CD70 and CD82+ progenitor NP cells (Pro NPC) were identified. In the late stage of IDD, the IR NPC and Fc NPC account for a large proportion of NPC. Importantly, immune cells including macrophages, T cells, myeloid progenitors, and neutrophils were also identified, and further analysis showed that significant intercellular interaction between macrophages and Pro NPC occurred via MIF (macrophage migration inhibitory factor) and NF-kB signaling pathways during the progression of IDD. In addition, dynamic polarization of macrophage M1 and M2 cell subtypes was found in the progression of IDD, and gene set functional enrichment analysis suggested a significant role of the macrophage polarization in regulating cell metabolism, especially the Pro NPC. Finally, we found that the NP cells in the late degenerative stage were mainly composed of the cell types related to inflammatory and endoplasmic reticulum (ER) response, and fibrocartilaginous activity. Our results provided new insights into the identification of NP cell populations at single-cell resolution and at the relatively whole-transcriptome scale, accompanied by cellular communications between immune cells and NP cells, and discriminative markers in relation to specific cell subsets. These new findings present clues for effective and functional manipulation of human IDD-related bioremediation and healthcare.

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Section: Discussionsupporting

confidence: 94%

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Ling

Liu

Wang

et al. 2022

Front. Cell Dev. Biol.

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“…A single impact applied to the lumbar disc without causing structural damage to the lumbar spine also triggered significant upregulation of Piezo1, NLRP3 inflammatory vesicles, catabolic (MMP-9, MMP-13) and pro-inflammatory gene (IL-1β) expression and induced disc degeneration (IDD). Piezo1 inhibition reduces mechanical shock-induced activation of NLRP3 inflammasome and IL-1β expression in nucleus pulposus cells ( 95 ). In addition, G protein-coupled estrogen receptor attenuates mechanical stress-mediated apoptosis of chondrocytes in osteoarthritis via suppression of Piezo1 ( 96 ).…”

Section: Piezo1 Channel-mediated Chronic Inflammationmentioning

confidence: 99%

“…The function of Piezo1 and its downstream mechanism have obvious differences in various tissue inflammations. Piezo1-mediated Ca 2+ signaling participates in the occurrence and development of inflammation through a variety of signaling pathways ( Table 1 ), including the classic inflammation pathway Jak/Stat: IL-6 receptor family ( 56 , 120 ), TLR ( 9 , 42 ) and NF-κB ( 66 , 117 , 121 ); Inflammasome NLRP3 ( 66 , 95 ); Ca 2+ -sensitive MAPK family (ERK, JNK, P38) ( 116 , 120 , 122 , 123 ), AKT/mTOR ( 60 , 69 )、β1 integrin ( 18 ); As well as focal adhesion kinase (FAK) related to inflammation-related mechanical transformation ( 60 , 124 ), proline-rich tyrosine kinase2 (Pyk2) ( 125 ); Calcineurin (RACK1), calcium/calmodulin-dependent protein kinase II (CaMKII-Mst1/2-Rac) and calpain1 ( 18 ). Although the downstream mechanisms involved in Piezo1 are different in different organizations and occasions, they all eventually lead to inflammatory events.…”

Section: Mechanism Of Piezo1 Transducing Inflammatory Signalsmentioning

confidence: 99%

Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

Liu

Zheng

et al. 2022

Front. Immunol.

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Mechanical damage is one of the predisposing factors of inflammation, and it runs through the entire inflammatory pathological process. Repeated or persistent damaging mechanical irritation leads to chronic inflammatory diseases. The mechanism of how mechanical forces induce inflammation is not fully understood. Piezo1 is a newly discovered mechanically sensitive ion channel. The Piezo1 channel opens in response to mechanical stimuli, transducing mechanical signals into an inflammatory cascade in the cell leading to tissue inflammation. A large amount of evidence shows that Piezo1 plays a vital role in the occurrence and progression of chronic inflammatory diseases. This mini-review briefly presents new evidence that Piezo1 responds to different mechanical stresses to trigger inflammation in various tissues. The discovery of Piezo1 provides new insights for the treatment of chronic inflammatory diseases related to mechanical stress. Inhibiting the transduction of damaging mechanical signals into inflammatory signals can inhibit inflammation and improve the outcome of inflammation at an early stage. The pharmacology of Piezo1 has shown bright prospects. The development of tissue-specific Piezo1 drugs for clinical use may be a new target for treating chronic inflammation.

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“…Despite its regular occurrence over a lifetime, it is currently uncertain if IVDD can be initiated by Piezo1 under excessive stress. As for the role of Piezo1 in the IVDD process, Sun et al [ 30 ] reported that a single impact injury without structural impairment, similar to axial stress, can promote inflammatory response during IVDD process via Piezo1 activation. Moreover, Sun et al [ 31 ] demonstrated Piezo1 sensitization induced by mechanical stretch also increased the NLPR3 inflammasome in NP cells.…”

Section: Discussionmentioning

confidence: 99%

Excessive mechanical stress-induced intervertebral disc degeneration is related to Piezo1 overexpression triggering the imbalance of autophagy/apoptosis in human nucleus pulpous

et al. 2022

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Background Mechanical stress plays a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). The mechanosensitive Piezo1 ion channel can sense the changes in mechanical stress and convert the mechanical signals into chemical signals. This study aims to investigate the effect of Piezo1 on the mechanical stress-induced IVDD and explore the possible mechanism. Methods The expression of Piezo1 and collagen II in immunohistochemical staining, cervical curvature, and the stiffness of nucleus pulpous (NP) were performed in normal and degenerated human intervertebral discs. In the experiment, high-intensity compression was applied to mimic the mechanical environment of IVDD. The cell viability, matrix macromolecules, and pro-inflammatory cytokines were examined to investigate the effect of Piezo1 on mechanical stress-treated NP cells. Additionally, autophagy condition of NP cells was detected within high-intensity compression and/or the inhibitor of Piezo1, GsMTx4. Results The up-expression of Piezo1, down-expression of Col II, elevated stiffness of NP, and poor kyphosis were observed in degenerated human intervertebral discs. High-intensity stress significantly decreased cell viability and the synthesis of extracellular matrix but increased the expression of senescence-associated proteins (p53 and p16) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) by mitochondrial dysfunction and suppression of autophagy. However, GsMTx4 can partly attenuate these effects. Conclusion Piezo1 upregulation under excessive mechanical stress promotes the apoptosis, senescence, and pro-inflammatory cytokines of NP and leads to the loss of extracellular matrix by mitochondrial dysfunction and the suppression of autophagy; on the other hand, the inhibition of Piezo1 can partly alleviate these effects.

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Single Impact Injury of Vertebral Endplates Without Structural Disruption, Initiates Disc Degeneration Through Piezo1 Mediated Inflammation and Metabolism Dysfunction

Cited by 18 publications

References 41 publications

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Single-Cell RNA-Seq Analysis Reveals Macrophage Involved in the Progression of Human Intervertebral Disc Degeneration

Piezo1 Channels as Force Sensors in Mechanical Force-Related Chronic Inflammation

Excessive mechanical stress-induced intervertebral disc degeneration is related to Piezo1 overexpression triggering the imbalance of autophagy/apoptosis in human nucleus pulpous

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