Gene expression profile at single cell level of nucleus pulposus cells (NPCs) from the nucleus pulposus (NP) tissue in the mild degenerative intervertebral discs (MDD) and server degenerative intervertebral discs(SDD).
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE244889 | GEO | 2023/10/30
REPOSITORIES: GEO
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Project description:Lumbar degenerative disc diseases cause low back pain (LBP). The maintenance of the height and stability of the intervertebral disc (IVD) space is an effective treatment for LBP. The following study evaluated the effects of fibroblast injection on intervertebral disc degeneration (IDD) in a preclinical setting. Compared with the IDD group, the fibroblast treatment group demonstrated effective maintenance of IVD height, reduced endplate degeneration, and improved nuclear magnetic resonance signals and overall histological structure. In doing so, fibrotic IVDs maintained the stability and biomechanics of the vertebra. This finding is in agreement with clinical findings that human nucleus pulposus (NP) fibrosis is essential for the maintenance of IVD height and mechanical properties in patients following percutaneous endoscopic lumbar discectomy (PELD). Mechanistically, we demonstrated that injected fibroblasts not only proliferated but also induced NP cells to adopt a fibrotic phenotype via the secretion of TGF-β. Finally, to better mimic human conditions, the efficacy of autologous fibroblast injection in the treatment of IDD was further examined in a nonhuman primate cynomolgus monkey model due to their capacity for upright posture. We showed that the injection of fibroblasts could maintain the IVD height and rescue IVD signals in cynomolgus monkeys. Taken together, the results of our study reveal that autologous fibroblast injection can enhance the natural process of fibrosis during acute and subacute stages of stress-induced IDD. Fibrotic IVDs can maintain the stability, biological activity, and mechanical properties of the intervertebral space, thus providing a new direction for the treatment of intervertebral space-derived lumbar degenerative diseases.
| S-EPMC7015945 | biostudies-literature
Project description:The accumulation of metabolites in the intervertebral disc is regarded as an important inducement of intervertebral disc degeneration (IVDD). Lactate, a metabolite produced by the cellular anaerobic glycolysis process, has been proved to be closely associated with IVDD. However, little was known about the role of lactate in nucleus pulposus cells (NPCs) senescence. This study attempted to investigate the effect and molecular mechanism of lactate on NPCs senescence in vitro and in vivo. A puncture-induced disc degeneration model was established in rats. Metabolomics analysis proved that lactate was significantly increased in the rat degenerated intervertebral disc. Eliminating extra lactate using lactate oxidase (LOx)-overexpressing lentivirus alleviated the progression of IVDD. In vitro experiments showed that high concentration lactate could induce senescence and oxidative stress in NPCs. High-throughput RNA sequencing (RNA-seq) results and bioinformatic analysis exhibited that lactate-stimulated NPCs senescence may be related to the PI3K/Akt signaling pathway. Further study verified that high concentration lactate could induce NPCs senescence and oxidative stress via inhibiting PI3K/Akt signaling and downstream Akt/p21/p27/cyclinD1 and Akt/Nrf2/HO-1 pathway. Utilizing molecular docking, we found that lactate may suppress the Akt phosphoactivation via binding to Lys39 and Leu52 in the PH domain of Akt. In conclusion, this study illuminates that lactate could promote the senescence of NPCs to aggravate IVDD by suppressing the PI3K/Akt signaling pathway and the expression of its downstream genes. These results highlight the involvement of lactate NPCs senescence, which may become a novel potential therapeutic target for the treatment of IVDD.
2022-12-06 | GSE219145 | GEO
Project description:It is well documented that low back pain is a common condition and the leading cause of disability globally. A widely recognised contributor to low back pain is intervertebral disc degeneration (IVDD), which is the major cause of a series of degenerative disc diseases. Recently, it has been reported that circRNAs are involved in the development of IVDD. However, the mechanisms by which m6A modifies circRNA in nucleus pulposus cells remain poorly understood. Here, we aim to identify differentially expressed m6A circRNAs in degenerative nucleus pulposus cells and figure out how the circRNAs regulate IVDD progression and the m6A methylation functions.
2023-08-21 | GSE199993 | GEO
Project description:Cell-based regenerative approaches have been suggested as primary or adjuvant procedures for the treatment of degenerated intervertebral disc (IVD) diseases. Our aim was to evaluate the regenerative and immunogenic properties of mildly and severely degenerated cervical nucleus pulposus (NP) cells with regard to cell isolation, proliferation and differentiation, as well as to cell surface markers and co-cultures with autologous or allogeneic peripheral blood mononuclear cells (PBMC) including changes in their immunogenic properties after 3-dimensional (3D)-culture. Tissue from the NP compartment of 10 patients with mild or severe grades of IVD degeneration was collected. Cells were isolated, expanded with and without basic fibroblast growth factor and cultured in 3D fibrin/poly (lactic-co-glycolic) acid transplants for 21 days. Real-time reverse-transcription polymerase chain reaction (RT-PCR) showed the expression of characteristic NP markers ACAN, COL1A1 and COL2A1 in 2D- and 3D-culture with degeneration- and culture-dependent differences. In a 5,6-carboxyfluorescein diacetate N-succinimidyl ester-based proliferation assay, NP cells in monolayer, regardless of their grade of degeneration, did not provoke a significant proliferation response in T cells, natural killer (NK) cells or B cells, not only with donor PBMC, but also with allogeneic PBMC. In conjunction with low inflammatory cytokine expression, analyzed by Cytometric Bead Array and fluorescence-activated cell sorting (FACS), a low immunogenicity can be assumed, facilitating possible therapeutic approaches. In 3D-culture, however, we found elevated immune cell proliferation levels, and there was a general trend to higher responses for NP cells from severely degenerated IVD tissue. This emphasizes the importance of considering the specific immunological alterations when including biomaterials in a therapeutic concept. The overall expression of Fas receptor, found on cultured NP cells, could have disadvantageous implications on their potential therapeutic applications because they could be the targets of cytotoxic T-cell activity acting by Fas ligand-induced apoptosis.
| S-EPMC4438063 | biostudies-literature
Project description:Intervertebral disc degeneration (IDD), a major cause of low back pain, occurs with ageing. The core of the intervertebral disc, the nucleus pulposus (NP), embedded in a proteoglycan-rich and gelatinous matrix, is derived from the embryonic notochord. With IDD, the NP becomes fibrous, containing fewer cells, which are fibroblastic and of unknown origin. Here, we used a lineage tracing strategy to investigate the origin of cells in the NP in injury-induced mouse IDD. We established a Foxa2 notochord-specific enhancer-driven Cre transgenic mouse model (Foxa2mNE-Cre) that acts only in the embryonic to foetal period up to E14.5, to genetically label notochord cells with enhanced green fluorescent protein (EGFP). When this mouse is crossed to one carrying a Cre recombinase reporter, Z/EG, EGFP-labelled NP cells are present even at 2 years of age, consistent with their notochordal origin. We induced tail IDD in Foxa2mNE-Cre; Z/EG mice by annulus puncture and observed the degenerative changes for 12 weeks. Soon after puncture, EGFP-labelled NP cells showed strong Col2a1+ expression unlike uninjured control NP. Later, accompanying fibrotic changes, EGFP-positive NP cells expressed fibroblastic and myofibroblastic markers such as Col1a1, ASMA, FAPA and FSP-1. The number of EGFP+ cells co-expressing the fibroblastic markers increased with time after puncture. Our findings suggest resident NP cells initially upregulate Col2a1+ and later transform into fibroblast-like cells during injury-mediated disc degeneration and remodelling. This important discovery concerning the cellular origin of fibrotic pathology in injury-induced IDD has implications for management in disease and ageing.
| S-EPMC7681061 | biostudies-literature
Project description:Intervertebral disc (IVD) degeneration is a pathological process, which may lead to lower back pain. The present study aimed to investigate the pathogenesis of IVD degeneration. GSE42611 was downloaded from Gene Expression Omnibus, including 4 nucleus pulposus samples isolated from degenerated IVDs and 4 nucleus pulposus samples separated from normal IVDs. The differentially expressed genes (DEGs) between the degenerated and normal samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted separately for the upregulated and downregulated genes, using Database for Annotation, Visualization and Integrated Discovery software. In addition, protein‑protein interaction (PPI) networks were constructed using the Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. Finally, module analyses were conducted for the PPI networks using the MCODE plug‑in in Cytoscape. A total of 558 DEGs were identified in the degenerated nucleus pulposus cells: 253 upregulated and 305 downregulated. Pathway enrichment analysis revealed that downregulated thrombospondin 1 (THBS1) was enriched in extracellular matrix‑receptor interaction. Interleukin (IL)‑6 in the PPI network for the upregulated genes and vascular endothelial growth factor A (VEGFA) in the PPI network for the downregulated genes had higher degrees. Additionally, four modules (µM1, µM2, µM3 and µM4) were identified from the PPI network for the upregulated genes. Four modules (dM1, dM2, dM3 and dM4) were identified from the PPI network for the downregulated genes. In the dM2 module, collagen genes and integrin subunit α4 (ITGA4) may interact with each other. Additionally, functional enrichment indicated that collagen genes were enriched in extracellular matrix organization. In conclusion, IL‑6, VEGFA, THBS1, ITGA4 and collagen genes may contribute to the progression of IVD degeneration. These results suggested that the manipulation of these genes and their products may have potential as a novel therapeutic strategy for the treatment of patients with IVD.
| S-EPMC5482069 | biostudies-literature
Project description:Disc Degeneration is a multifactorial disease which cause severe constant chronic pain. The development of disc degeneration could involve both genetic and environmental factors, so it's important to elucidate the difference in gene expression profiles between degenerative and non-degenerative discs from elderly patients and younger patients, respectively. Affymetrix GeneChip Human Genome U133A Array was used to derive gene expression profiles and identified genes that would express at significantly different levels between degenerative and non-degenerative samples. Human intervertebral disc tissues were harvested from elderly and younger patients with degenerative disc disease and adolescent idiopathic scoliosis, respectively, for RNA extraction and hybridization on Affymetrix microarrays. One degenerative sample was compared to one non-degenerative sample in the same microarray run, and comparative analyses were performed in triplicate. Gene whose expression levels varied across the samples with a log ratio >0.5 or <-0.5 were selected as the genes related to disc degeneration.
2012-05-31 | E-GEOD-34095 | biostudies-arrayexpress
Project description:Disc Degeneration is a multifactorial disease which cause severe constant chronic pain. The development of disc degeneration could involve both genetic and environmental factors, so it's important to elucidate the difference in gene expression profiles between degenerative and non-degenerative discs from elderly patients and younger patients, respectively. Affymetrix GeneChip Human Genome U133A Array was used to derive gene expression profiles and identified genes that would express at significantly different levels between degenerative and non-degenerative samples.
2012-06-01 | GSE34095 | GEO
Project description:A comprehensive understanding of the cellular heterogeneity and molecular mechanisms underlying the development, homeostasis, and disease of human intervertebral disks (IVDs) remains challenging. Here, the transcriptomic landscape of 108 108 IVD cells was mapped using single-cell RNA sequencing of three main compartments from young and adult healthy IVDs, including the nucleus pulposus (NP), annulus fibrosus, and cartilage endplate (CEP). The chondrocyte subclusters were classified based on their potential regulatory, homeostatic, and effector functions in extracellular matrix (ECM) homeostasis. Notably, in the NP, a PROCR+ resident progenitor population showed enriched colony-forming unit-fibroblast (CFU-F) activity and trilineage differentiation capacity. Finally, intercellular crosstalk based on signaling network analysis uncovered that the PDGF and TGF-β cascades are important cues in the NP microenvironment. In conclusion, a single-cell transcriptomic atlas that resolves spatially regulated cellular heterogeneity together with the critical signaling that underlies homeostasis will help to establish new therapeutic strategies for IVD degeneration in the clinic.
| S-EPMC8368097 | biostudies-literature
Project description:Intervertebral disc degeneration (IDD) is an important factor leading to low back pain, but the underlying mechanisms remain poorly understood. Compared with normal nucleus pulposus (NP) tissues, the expression of circ-GRB10 was downregulated in IDD. Furthermore, overexpression of circ-GRB10 inhibited NP cell apoptosis. circ-GRB10 could sequester miR-328-5p, which could potentially lead to the upregulation of target genes related to cell proliferation via the ErbB pathway. In conclusion, the present study revealed that circ-GRB10/miR-328-5p/ERBB2 signaling pathway is involved in IDD development, suggesting that circ-GRB10 might be a novel therapeutic target for IDD.
| S-EPMC5833826 | biostudies-literature