Cytosolic escape of mitochondrial DNA triggers cGAS-STING-NLRP3 axis-dependent nucleus pulposus cell pyroptosis

Experimental & Molecular Medicine, Journal Year: 2022, Volume and Issue: 54(2), P. 129 - 142

Published: Feb. 1, 2022

Abstract Low back pain (LBP) is a major musculoskeletal disorder and the socioeconomic problem with high prevalence that mainly involves intervertebral disc (IVD) degeneration, characterized by progressive nucleus pulposus (NP) cell death development of an inflammatory microenvironment in NP tissue. Excessively accumulated cytosolic DNA acts as damage-associated molecular pattern (DAMP) monitored cGAS-STING axis to trigger immune response many degenerative diseases. NLRP3 inflammasome-dependent pyroptosis type programmed promotes chronic tissue degeneration. However, relationship between inflammasome-induced pathogenesis IVD degeneration remains unclear. Here, we used magnetic resonance imaging (MRI) histopathology demonstrate cGAS, STING, are associated degree Oxidative stress induced activation inflammasome-mediated STING-dependent manner human cells. Interestingly, canonical morphological functional characteristics mitochondrial permeability transition pore (mPTP) opening escape (mtDNA) were observed cells under oxidative stress. Furthermore, administration specific pharmacological inhibitor mPTP self-mtDNA leakage effectively reduced pyroptotic microenvironmental inflammation vitro progression rat needle puncture model. Collectively, these data highlight critical roles cGAS-STING-NLRP3 provide promising therapeutic approaches for discogenic LBP.

Language: Английский

---

Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration

Cells, Journal Year: 2021, Volume and Issue: 10(9), P. 2241 - 2241

Published: Aug. 29, 2021

Intervertebral disc degeneration (IVDD) occurs as a result of an imbalance the anabolic and catabolic processes in intervertebral disc, leading to alteration composition extracellular matrix (ECM), loss nucleus pulposus (NP) cells, excessive oxidative stress inflammation. Degeneration IVD naturally with age, but mechanical trauma, lifestyle factors certain genetic abnormalities can increase likelihood symptomatic disease progression. IVDD, often referred degenerative (DDD), poses increasingly substantial financial burden due aging population increasing incidence obesity United States. Current treatments for IVDD include pharmacological surgical interventions, these lack ability stop progression restore functionality IVD. Biological therapies have been evaluated show varying degrees efficacy reversing long-term. Stem cell-based shown promising results regeneration IVD, face both biological ethical limitations. Exosomes play important role intercellular communication, stem cell-derived exosomes maintain therapeutic benefit their origin cells without associated risks. This review highlights current state research on use stem-cell derived treatment IVDD.

Language: Английский

---

Cartilage endplate stem cells inhibit intervertebral disc degeneration by releasing exosomes to nucleus pulposus cells to activate Akt/autophagy

Stem Cells, Journal Year: 2021, Volume and Issue: 39(4), P. 467 - 481

Published: Jan. 18, 2021

Abstract Degeneration of the cartilage endplate (CEP) induces intervertebral disc degeneration (IVDD). Nucleus pulposus cell (NPC) apoptosis is also an important exacerbating factor in IVDD, but cascade mechanism IVDD not clear. We investigated NPCs and when stimulated by normal stem (CESC)-derived exosomes (N-Exos) degenerated CESC-derived (D-Exos) vitro vivo. Tert-butyl hydroperoxide (TBHP) was used to induce inflammation CESCs. The bioinformatics differences between N-Exos D-Exos were analyzed using mass spectrometry, heat map, Kyoto Encyclopedia Genes Genomes (KEGG) enrichment analysis. NPC examined TUNEL staining. involvement AKT autophagy signaling pathways inhibitor LY294002. Magnetic resonance imaging, Western blotting, immunofluorescence staining evaluate therapeutic effects rats with IVDD. TBHP effectively induced CEP rat. more conducive activation than D-Exos. apoptotic rate decreased obviously after treatment compared inhibited attenuated rat via pathways. These results are first findings confirm that delayed progression exosomes. on inhibition slowing effective due PI3K/AKT/autophagy pathway, which explained increase incidence CEP.

Language: Английский

---

Oxidative stress in intervertebral disc degeneration: Molecular mechanisms, pathogenesis and treatment

Cell Proliferation, Journal Year: 2023, Volume and Issue: 56(9)

Published: March 13, 2023

Abstract Low back pain (LBP) is a leading cause of labour loss and disability worldwide, it also imposes severe economic burden on patients society. Among symptomatic LBP, approximately 40% caused by intervertebral disc degeneration (IDD). IDD the pathological basis many spinal degenerative diseases such as herniation stenosis. Currently, therapeutic approaches for mainly include conservative treatment surgical treatment, neither which can solve problem from root terminating process (IVD). Therefore, further exploring pathogenic mechanisms adopting targeted strategies one current research hotspots. complex pathophysiological processes IDD, oxidative stress considered main factor. The delicate balance between reactive oxygen species (ROS) antioxidants essential maintaining normal function survival IVD cells. Excessive ROS levels damage to macromolecules nucleic acids, lipids, proteins cells, affect cellular activities functions, ultimately lead cell senescence or death. This review discusses potential role in understand provides IDD.

Language: Английский

---

Intervertebral disc degeneration—Current therapeutic options and challenges

Frontiers in Public Health, Journal Year: 2023, Volume and Issue: 11

Published: July 6, 2023

Degeneration of the intervertebral disc (IVD) is a normal part aging. Due to spine's declining function and development pain, it may affect one's physical health, mental socioeconomic status. Most degeneration (IVDD) therapies today focus on symptoms low back pain rather than underlying etiology or mechanical disc. The deteriorated typically not restored by conservative surgical that largely correcting structural abnormalities. To enhance clinical outcome quality life patient, several therapeutic modalities have been created. In this review, we discuss genetic environmental causes IVDD describe promising modern endogenous exogenous approaches including their applicability relevance process.

Language: Английский

---

Role of macrophage in intervertebral disc degeneration

Bone Research, Journal Year: 2025, Volume and Issue: 13(1)

Published: Jan. 23, 2025

Language: Английский

---

Extracellular Vesicles as an Emerging Treatment Option for Intervertebral Disc Degeneration: Therapeutic Potential, Translational Pathways, and Regulatory Considerations

Advanced Healthcare Materials, Journal Year: 2021, Volume and Issue: 11(5)

Published: July 23, 2021

Emergent approaches in regenerative medicine look toward the use of extracellular vesicles (EVs) as a next-generation treatment strategy for intervertebral disc (IVD) degeneration (IVDD) because their ability to attenuate chronic inflammation, reduce apoptosis, and stimulate proliferation number tissue systems. Yet, there are no Food Drug Administration (FDA)-approved EV therapeutics market with an indication IVDD, which motivates this article review current state field provide IVD-specific framework assess its efficacy. In systematic review, 29 preclinical studies that investigate EVs relation IVD identified, additionally, regulatory approval process is reviewed effort accelerate emerging EV-based FDA submission timeline-to-market. The majority focus on nucleus pulposus responses treatment, where main findings show stem cell-derived can decelerate progression IVDD molecular, cellular, organ level. also highlight importance parent cell's pathophysiological differentiation state, affects downstream therapeutic outcomes. This substantiates promising cell-free treat enhance endogenous repair.

Language: Английский

---

Injectable cartilage matrix hydrogel loaded with cartilage endplate stem cells engineered to release exosomes for non-invasive treatment of intervertebral disc degeneration

Bioactive Materials, Journal Year: 2021, Volume and Issue: 15, P. 29 - 43

Published: Dec. 21, 2021

Low back pain, mainly caused by intervertebral disc degeneration (IVDD), is a common health problem; however, current surgical treatments are less than satisfactory. Thus, it essential to develop novel non-invasive methods for IVDD treatment. Here, we describe therapeutic strategy inhibit injecting hydrogels modified with the extracellular matrix of costal cartilage (ECM-Gels) that loaded endplate stem cells (CESCs). After CESCs overexpressing Sphk2 (Lenti-Sphk2-CESCs) and injected near (CEP) rats in vivo, ECM-Gels produced Sphk2-engineered exosomes (Lenti-Sphk2-Exos). These penetrated annulus fibrosus (AF) transported into nucleus pulposus (NPCs). activated phosphatidylinositol 3-kinase (PI3K)/p-AKT pathway as well intracellular autophagy NPCs, ultimately ameliorating IVDD. This study provides efficient combinational treatment using injectable express sustained release functional exosomes.

Language: Английский

---

Mesenchymal Stem Cell-Derived Exosomes and Intervertebral Disc Regeneration: Review

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(13), P. 7306 - 7306

Published: June 30, 2022

Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as whole. IVDD occurs result aging, mechanical trauma, lifestyle factors, certain genetic abnormalities, leads to loss nucleus pulposus, alteration in the composition extracellular matrix, excessive oxidative stress, inflammation intervertebral disc. Pharmacological surgical interventions are considered boon for treatment IVDD, but effectiveness those strategies limited. Mesenchymal stem cells (MSCs) have recently emerged possible promising regenerative therapy due their paracrine effect, restoration degenerated cells, capacity differentiation into cells. Recent investigations shown that pleiotropic effect MSCs not related mediated by secretion soluble factors. Early studies demonstrated MSC-derived exosomes therapeutic potential treating promoting cell proliferation, tissue regeneration, modulation inflammatory response, reduced apoptosis. This paper highlights current state field with further future developments, applications, challenges.

Language: Английский

---

Application of mesenchymal stem cell-derived exosomes from different sources in intervertebral disc degeneration

Frontiers in Bioengineering and Biotechnology, Journal Year: 2022, Volume and Issue: 10

Published: Oct. 7, 2022

Intervertebral disc degeneration (IVDD) is a main cause of lower back pain, leading to psychological and economic burdens patients. Physical therapy only delays pain in patients but cannot eliminate the IVDD. Surgery required when patient tolerate or has severe neurological symptoms. Although surgical resection IVD decompression laminae eliminates diseased segment, it damages adjacent normal IVD. There also risk re-protrusion after removal. Cell played crucial role development regenerative medicine. transplantation promotes regeneration degenerative tissue. However, owing lack vascular structure IVD, sufficient nutrients be provided for transplanted mesenchymal stem cells (MSCs). In addition, dead release harmful substances that aggravate Extracellular vesicles (EVs) have been extensively studied as an emerging therapeutic approach. EVs generated by paracrine MSCs retain potential serve carriers deliver their contents target regulate cell activity. Owing double-layered membrane structure, low immunogenicity no immune rejection. Therefore, are considered modality they limited mass production loading rates. this review, advantages introduced, application MSC-EVs IVDD discussed. The current limitations future applications described.

Language: Английский

---