Single-cell transcriptomics reveals heterogeneity and intercellular crosstalk in human intervertebral disc degeneration

Wang, Dandan; Li, ZiZhang; Huang, Weimin; Cao, Shengnan; Xie, Liangyu; Chen, Yuanzhen; Li, Huazhong; Wang, Lei; Chen, Xiaoshu; Yang, Jinfu

doi:10.1016/j.isci.2023.106692

Cited by 11 publications

(7 citation statements)

References 56 publications

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“…We examined the cellular heterogeneity and fibroblastic cell entities by an integrative analysis of 4 published single-cell RNA sequencing (scRNA-seq) data derived from cells isolated from NP tissues 7,12,14 or recognized as NP cells 11 . The datasets consist of 6 non-degenerative human IVDs, 13 mildly (Pfirrmann II-III) and 12 severely (Pfirrmann IV-V) degenerative human IVDs ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, tracing study indicated that not all myofibroblastic cells are derived from local cells 4 , implying alternative origins of effector cells for NP fibrosis. In line with this notion, single cell transcriptomic studies have revealed that the NP of human degenerative IVDs 7,[11][12][13][14] and animal model of IDD 6 contain cell types other than IVD cells. These include endothelial cells, myeloid granulocytic suppressor cells, CCR2 + monocytes and derivatives of macrophages.…”

Section: Introductionmentioning

confidence: 81%

“…NPC are conventionally defined as collagen II-, aggrecan-and Sox9-expressing cells. Recent studies of single-cell transcriptome have indicated cell heterogeneity in the human NP, which contains cell populations expressing notochordal, chondrogenic, and fibroblastic phenotypes 7,[11][12][13][14] . Our metaanalysis of the human disc scRNA-seq datasets has outlined the commonly featured NPC hierarchy and stratified their fibroblastic subtypes.…”

Section: Discussionmentioning

confidence: 99%

“…COL1A1 + FibroNP is previously defined as adhesion/fibroNPC 12 or C4 NPC 7 . The FibroNP population was not reported in Wang et al scRNAseq dataset, possibly because their cells were derived from the whole disc tissue without NP isolation and therefore may have dominated by COL1A1 + AF cells 11 . Nonetheless, they defined the FibroNP genes (POSTN, COL1A1, COL3A1 and TMSB4X) in MK167 + progenitor and NP progenitor cells (Supplementary Table 1), implying the fibroblast presence within the two NP subtypes.…”

Section: Discussionmentioning

confidence: 99%

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Monocytic fibrocyte-like cell enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity

Sun,

Peng,

et al. 2024

Preprint

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Nucleus pulposus (NP) undergoes fibrosis, leading to structural and mechanical anomalies of intervertebral discs that prone to degeneration. Fibroblastic cells emerge and account for NP fibrosis, yet their nature and origin remain elusive. Degenerative NP cells are highly heterogenous and may contain immune cells. By meta-analysis of single-cell data, we here showed an enrichment of hematopoietic fibrocyte-like cells, defined by CD45 and collagen I dual positivity, in human NP specimens which increases with degeneration severity. We identified fibrocytes subtypes with a myofibroblast differentiation capacity in NP fibrosis. These fibrocytes were recruited in NP fibrosis mediated by injury-induced mouse disc degeneration. Monocyte depletion in CD11b-DTR mice attenuated NP fibrosis and myofibroblast generation, and prevented disc height loss and histomorphological abnormalities. Our findings suggest that fibrocyte-like cells may mediate NP fibrosis and therefore be a potential target for modifying disc degeneration and promoting its repair.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Monocytic fibrocyte-like cell enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity

Sun,

Peng,

et al. 2024

Preprint

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“…17,52 The exact mechanism relating FGF4 overexpression to premature IVDD is not defined, however recent single cell RNASeq studies defining the heterogenous cellular populations in the embryonic and adult intervertebral disc might provide a framework for potential mechanisms. [66][67][68][69] Whatever the mechanism is determined to entail, premature degeneration of the IVD in chondrodystrophic dogs does not preclude other mechanisms for FCE pathogenesis since FCE is frequently documented in older non chondrodystrophic breeds where similar age-related NP degeneration is also likely to be present. 70,71 Developmental differences in vascular anatomy of the disc, vertebra, and spinal cord in chondrodystrophic dogs might also be nonpermissive to entry of fibrocartilage, and/or subsequent passage of the material to clinically relevant areas.…”

Section: Discussionmentioning

confidence: 99%

Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs

Embersics,

Bannasch,

Batcher

et al. 2023

Veterinary Internal Medicne

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BackgroundFibrocartilaginous embolic myelopathy (FCE) is a well‐documented condition in dogs although rarely reported in chondrodystrophic breeds. Genetic associations have not been defined.ObjectivesDefine the association of the chondrodystrophy‐associated FGF4L2 retrogene with histopathologically confirmed cases of FCE.AnimalsNinety‐eight dogs with a histopathologic diagnosis of FCE.MethodsRetrospective multicenter study. Dogs were genotyped for the FGF4L2 and FGF4L1 retrogenes using DNA extracted from formalin‐fixed, paraffin‐embedded tissue. Associations between breed, FCE and retrogene status were investigated with reference to a hospital population and known breed and general population allele frequencies.ResultsFGF4L2 genotype was defined in 89 FCE cases. Fibrocartilaginous embolic myelopathy was present in 22 dogs from FGF4L2‐segregating breeds with allele frequencies of ≥5%; however, all dogs were wild type. Two Labrador retrievers with FCE carried FGF4L2 alleles. Frequency of the FGF4L2 allele was significantly (P < .001) and negatively associated with FCE relative to predicted hospital‐population dogs. FCE was overrepresented in Boxer, Great Dane, Yorkshire Terrier, Bernese Mountain Dog, Miniature Schnauzer, Rottweiler, and Shetland Sheepdog breeds.Conclusions and Clinical ImportanceStudy data based on genotypically and histopathologically defined cases support the historical observation that FCE is uncommon in chondrodystrophic dog breeds. FGF4 plays an important role in angiogenesis and vascular integrity; anatomical studies comparing chondrodystrophic and non‐chondrodystrophic dogs might provide insight into the pathogenesis of FCE.

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Silencing of secreted phosphoprotein 1 attenuates sciatic nerve injury‐induced neuropathic pain: Regulating extracellular signal‐regulated kinase and neuroinflammatory signaling pathways

Xie,

Lu,

et al. 2024

Immunity Inflam & Disease

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BackgroundNeuropathic pain (NP) is a chronic pathological pain that affects the quality of life and is a huge medical burden for affected patients. In this study, we aimed to explore the effects of secreted phosphoprotein 1 (SPP1) on NP.MethodsWe established a chronic constriction injury (CCI) rat model, knocked down SPP1 via an intrathecal injection, and/or activated the extracellular signal‐regulated kinase (ERK) pathway with insulin‐like growth factor 1 (IGF‐1) treatment. Pain behaviors, including paw withdrawal threshold (PWT), paw withdrawal latency (PWL), lifting number, and frequency, were assessed. After sacrificing rats, the L4‐L5 dorsal root ganglion was collected. Then, SPP1 levels were determined using quantitative polymerase chain reaction (qPCR) and western blot analysis. The levels of interleukin (IL)‐1β, tumor necrosis factor (TNF)‐α, IL‐6, IL‐10, epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and transforming growth factor (TGF)‐β were determined using qPCR and enzyme‐linked immunosorbent assay. The levels of ERK pathway factors were determined via western blot analysis.ResultsWe found that CCI decreased PWT and PWL, increased the lifting number and frequency, and upregulated SPP1 levels. The loss of SPP1 reversed these CCI‐induced effects. Additionally, CCI upregulated IL‐1β, TNF‐α, IL‐6, EGF, and VEGF levels, downregulated TGF‐β levels, and activated the ERK pathway, while silencing of SPP1 abrogated these CCI‐induced effects. Moreover, IGF‐1 treatment reversed the effects of SPP1 loss.ConclusionsThe data indicate that silencing SPP1 attenuates NP via inactivation of the ERK pathway, suggesting that SPP1 may be a promising target for NP treatment.

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Single-cell transcriptomics reveals heterogeneity and intercellular crosstalk in human intervertebral disc degeneration

Cited by 11 publications

References 56 publications

Monocytic fibrocyte-like cell enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity

Monocytic fibrocyte-like cell enrichment and myofibroblastic adaptation causes nucleus pulposus fibrosis and associates with disc degeneration severity

Association of the FGF4L2 retrogene with fibrocartilaginous embolic myelopathy in dogs

Silencing of secreted phosphoprotein 1 attenuates sciatic nerve injury‐induced neuropathic pain: Regulating extracellular signal‐regulated kinase and neuroinflammatory signaling pathways

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