Irisin ameliorates the progression of intervertebral disc degeneration via LATS/YAP/CTGF signaling.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE203068 | GEO | 2025/04/26
REPOSITORIES: GEO
Similar Datasets
Project description:Background and aims Determining the transcriptomes and molecular mechanism underlying human degenerative nucleus pulposus (NP) is of critical importance for treating intervertebral disc degeneration (IDD). Here, we aimed to elucidate the detailed molecular mechanism of NP ossification and IDD using single-cell RNA sequencing. Methods Single-cell RNA-seq and bioinformatic analysis were performed to identify NP cell populations with gene signatures, biological processes and pathways, and subpopulation analysis, RNA velocity analysis, and cell-to-cell communication analysis were performed in four IDD patients. We also verified the effects of immune cells on NP ossification using cultured NP cells and a well-established rat IDD model. Results We identified five cell populations with gene expression profiles in degenerative NP at single-cell resolution. GO database analysis showed that degenerative NP-associated genes were mainly enriched in extracellular matrix organization, immune response, and ossification. Gene set enrichment analysis showed that rheumatoid arthritis signaling, antigen processing and presentation signaling were activated in the blood cell cluster. We revealed that stromal cells, which are progenitor cells, differentiated toward an ossification phenotype and delineated interactions between immune cells (macrophages and T cells) and stromal cells. Immune factors such as TNF-α, CD74 and CCL-3 promoted the differentiation of stromal cells toward an ossification phenotype in vitro. Blocking TNF-α with a specific inhibitor successfully reversed NP ossification and modified NP morphology in vivo. Conclusions Our study revealed an increase in macrophages and T cells in degenerative NP, which induced stromal cell differentiation toward an ossification phenotype, and contributed to the identification of a novel therapeutic target to delay IDD.
2023-06-01 | GSE233666 | GEO
Project description:Progressive loss of nucleus pulposus cells (NPCs) is associated with the onset of intervertebral disc degeneration (IDD). Transplantation of NPCs, derived from human pluripotent stem cells including hESC/iPSCs, may offer a novel therapy for IDD. To date, effective in vitro differentiations of notochordal and NP cells remained to be demonstrated. Towards this end, we developed a three-step protocol to directly differentiate hESC/iPSC towards mesodermal, then notochordal and finally NPCs. Our results showed that notochordal-like cells (NCCs) were successfully derived from the first two-steps of the protocol. Furthermore, these cells could be differentiated into NPCs. These NPCs expressed the tyrosine kinase receptor Tie2 (Tie2), disialoganglioside 2 (GD2), collagen II and aggrecan. Genome-wide transcriptomic analyses by sequencing (RNA-seq) revealed the expression of a wide array of known NP markers, extracellular matrix (ECM) genes, up-stream regulators and pathways. Cross-comparison of in vitro RNA-seq profiles with in vivo human NP data confirmed the in vitro NPCs are significantly more similar to in vivo NP than hESC/iPSCs. Transplantation of NPCs effectively attenuated disc injury in a rat model of IDD. We utilized CRISPR/Cas9 to seamlessly knock in an enhanced green fluorescent protein (eGFP) to the loci of the Noto gene in ESCs for NCC generation. Our study achieved effective notochordal differentiation and provided transcriptomic insights into the use of human ESC/iPSCs.
2019-12-31 | GSE122429 | GEO
Project description:Dysregulation of microRNAs (miRNAs) plays a critical role in the development of intervertebral disc degeneration (IDD). In this study, we present evidence from in vitro and in vivo research to elucidate the mechanism underlying the role of miR-760 in IDD. miRNA microarray and quantitative reverse transcription-polymerase chain reaction were used to determine the miRNA profiles in patients with IDD. Functional analysis was performed to evaluate the role of miR-760 in the pathogenesis of IDD. Luciferase reporter and western blotting assays were used to confirm the miRNA targets. The expression of miR-760 was significantly decreased in degenerative nucleus pulposus (NP) cells and negatively correlated with disc degeneration grade. Functional assays demonstrated that miR-760 delivery significantly increased NP cell proliferation and promoted the expression of collagen II and aggrecan. Moreover, MyD88 was identified as a target gene of miR-760. miR-760 effectively suppressed MyD88 expression by interacting with the 3′-untranslated region, which was abolished by miR-760 binding site mutations. An in vivo experiment using an IDD mouse model showed that the upregulation of miR-760 could effectively suspend IDD. Therefore, miR-760 was found to play an important role in IDD and can be used as a promising therapeutic target for the treatment of patients with IDD.
2022-03-17 | E-MTAB-11554 | biostudies-arrayexpress
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
2021-08-11 | GSE179078 | GEO
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
2021-08-11 | GSE174211 | GEO
Project description:Identifying secreted mediators driving the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer’s disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the exercise benefits on cognitive function. Genetic deletion of FNDC5/irisin (global F5KO mice) impairs cognitive function in exercise, aging, and AD. Diminished pattern separation in F5KOs can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KOs, adult-born neurons in the dentate gyrus are morphologically, transcriptionally, and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral administration, resulting in enrichment of central irisin, was sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of cognitive benefits of exercise and potential therapeutic for treating cognitive disorders including AD.
2021-08-11 | GSE174210 | GEO
Project description:Irisin ameliorates the progression of intervertebral disc degeneration via LATS/YAP/CTGF signaling.
| PRJNA838468 | ENA
Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
2025-03-19 | GSE290271 | GEO
Project description:The discectomy-induced ferroptosis stress on nucleus pulposus cells (NPCs) is a major cause for postoperative lumbar disc herniation (LDH) recurrence and intervertebral disc degeneration (IDD). Surprisingly, we discovered that nucleus pulposus progenitor cells (NPPCs) could transmit their ferroptosis-resistant phenotype to recipient NPCs through exosome-dependent cell-cell communication while identifying miR-221-3p as the primary anti-ferroptosis effector molecule therein. Based on these findings, we first developed a synthetically-tailored NPPC-derived exosomes with enhanced miR-221-3p expression and NPC uptake capacity through molecular and cellular engineering, which were then integrated into an injectable hydrogel based on extracellular matrix (ECM) analogues. The ECM-mimetic hydrogel (HACS) serves as a biomimetic filler for the post-operative care of herniated discs, which could be facilely injected into the discectomy-established nucleus pulposus (NP) cavity for localized treatment. HACS-mediated in-situ exosome release in the NP cavity enabled marked ferroptosis inhibition in NPCs that not only prevented LDH recurrence but also reversed the IDD symptoms, leading to robust restoration of NP structure and functions. This study offers a promising approach for the treatment of herniated discs with translational potential.
2025-03-19 | GSE290270 | GEO
Project description:The heterogeneity of nucleus pulposus cells (NPCs) and the molecular mechanisms underlying NP degeneration is still unclear. We performed unbiased transcriptome-wide single-cell RNA sequencing (scRNA-seq) on progressing degenerative grades of human NP. Cell subsets, their gene signatures, differentiation trajectory, and cell interactions were determined and characterized.We uncover seven populations of human NP cells and referred to these novel cell clusters with markers and their distinct functions. Monocle pseudospace, cytoTRACE, and scVelo analysis showed potential transition among cell subsets. We revealed novel markers for NP progenitors (NPPs), and found a close relationship between NPPs and fibrosis NP (FNPs). Neutrophils showed heterogeneity, which may be a resultsresult of activation and maturation. Identified granulocytic myeloid-derived suppressor cells (G- MDSCs) are correlated with disease progression. CD11b, OLR1, and CD24 were shown to be the markers in NP-derived G-MDSCs.Our study revealing NPCs type complexity and phenotypic characteristics of immune cells inside NP, providing new insights and clues for treatment of IVDD.
2021-12-26 | GSE165722 | GEO