Mesenchymal stromal/stem cell (MSC)-derived exosomes are nanoscale extracellular vesicles that have emerged as promising candidates for therapeutic and diagnostic applications because of their unique bioactive cargo, including proteins, lipids, and nucleic acids. These vesicles mitigate concerns of immunogenicity and tumorigenicity associated with MSC-based therapies and offer enhanced stability, higher scalability, and ease of modification. However, the use of MSC-derived exosomes in clinical practice is associated with challenges, including difficulties in isolation, characterization, and standardization. This review explores the biogenesis and structural properties of MSC-derived exosomes and discusses the molecular mechanisms underlying their therapeutic effects. It also discusses ongoing clinical trials on their applications in cancer, cardiovascular, neurological, and regenerative medicine. Preclinical and clinical data have demonstrated the potential of MSC-derived exosomes in enhancing tissue repair, reducing inflammation, and modulating immune responses. Despite these advancements, gaps in scalable production methods, regulatory guidelines, and therapeutic consistency must be addressed. Future innovations in bioengineering, manufacturing, and regulatory frameworks are essential to realize the full potential of MSC-derived exosomes in mainstream medicine.

The most common degenerative condition affecting the musculoskeletal system, and the leading cause of persistent low back pain, is intervertebral disc degeneration (IDD). IDD is increasingly common with age and has a variety of etiologic factors including inflammation, oxidative stress, extracellular matrix (ECM) degradation, and apoptosis that interact with each other to cause IDD. Because it is difficult to determine the exact pathogenesis of IDD, there is a lack of effective therapeutic agents. Melatonin has been intensively studied for its strong anti-inflammatory, antioxidant, and anti-apoptotic properties. Melatonin is a pleiotropic indole-stimulating hormone produced by the pineal gland, which can be used to treat a wide range of degenerative diseases. Therefore, melatonin supplementation may be a viable treatment for IDD. This article reviews the current mechanisms of IDD and the multiple roles regarding melatonin's anti-inflammatory, antioxidant, anti-apoptotic, and mitigating ECM degradation in IDD, incorporating new current research perspectives, as well as recent studies on drug delivery systems.

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and heme oxygenase 1 (HO‑1) attenuate intervertebral disc degeneration (IVDD). However, whether BMSC‑derived exosomes attenuate IVDD by delivering HO‑1 to nucleus pulposus (NP) cells remains to be elucidated. Mouse BMSCs were characterized by multilineage differentiation and surface marker molecule detection. Exosomes Exo and Exo‑HO‑1 were isolated from BMSCs and HO‑1‑overexpressing BMSCs by ultracentrifugation and characterized by observing their morphology, detecting the exosome marker proteins, tumor susceptibility gene 101 (TSG101) and CD63 and analyzing their particle size. Interleukin‑1 β (IL‑1β)‑stimulated NP cells were used as the IVDD cell model. The influence of Exo or Exo‑HO‑1 on IL‑1β‑urged apoptosis and senescence in NP cells was determined by flow cytometry, western blotting and senescence‑associated β‑galactosidase (SA‑β‑gal) staining. Exo and Exo‑HO‑1 did not vary in size or morphology. Exo‑HO‑1 markedly repressed IL‑1β‑prompted apoptosis in NP cells, accompanied with a prominent increase in Cleaved caspase 3 and Bax protein levels and a marked decrease in Bcl‑2 protein levels. Exo and Exo‑HO‑1 both decreased the number of SA‑β‑gal‑positive NP cells and arrested NP cells in the G1 phase. Exo‑HO‑1 had stronger effects than Exo, suggesting that Exo‑HO‑1 can weaken IL‑1β‑induced NP cell senescence. In addition, Exo and Exo‑HO‑1 repressed IL‑1β mediating the phosphorylation of p65 and nuclear translocation of p65. In conclusion, HO‑1‑overexpressing BMSC‑derived exosomes blocked the nuclear factor‑kappa B signaling in IL‑1β‑stimulated NP cells, thus impairing cell apoptosis and senescence.

Intervertebral disc degeneration is a multifactorial degenerative disease that poses a significant threat to the health of the elderly population. Current treatments primarily focus on physical therapy, medication, and surgery to alleviate symptoms associated with disc compression but do not address the progression of degeneration. Therefore, this review aimed to explore the potential of extracellular vesicle therapy as a novel preventive strategy to delay degeneration and enhance tissue repair in intervertebral discs. We cover the pathogenic mechanisms underlying intervertebral disc degeneration, including inflammation, apoptosis, pyroptosis, ferroptosis, autophagy dysregulation, and the roles of non-coding RNAs. Subsequently, we discussed the therapeutic potential of extracellular vesicles and their molecular components, such as proteins, RNAs, and lipids, in modulating these pathways to counter intervertebral disc degeneration. We provides a comprehensive review of the significant role of extracellular vesicle cargo in mediating repair mechanisms. It discusses the functional enhancement advantages exhibited by extracellular vesicles under current bioengineering modifications and drug loading. The challenges and future prospects of utilizing extracellular vesicle therapy to treat this degenerative condition are also summarized.

Suppressing bone mesenchymal stem cell (BMSC) ferroptosis is expected to optimize BMSCs-based therapy for intervertebral disc degeneration (IVDD). Our previous study revealed that Prominin-2 could protect against ferroptosis by decreasing cellular Fe2+ content and inhibiting transcription regulator protein BACH1 (BACH1) expression. In this study we probed the molecular mechanisms underlying the Prominin-2/BACH1 pathway in BMSC ferroptosis. Using an array of in vitro and in vivo experiments we found that heat shock factor protein 1 (HSF1) activates PROM2 (encoding protein Prominin-2) transcription and elevated Prominin-2 expression. Furthermore, we showed that Prominin-2 attenuates ferroptosis induced by tert-butyl hydroperoxide (TBHP) through promoting BACH1 ubiquitination and degradation. Inhibition of BACH1 expression reversed TBHP-stimulated down expression of glutaminase kidney isoform, mitochondrial (GLS), which plays a crucial role in protecting BMSCs against ferroptosis. Targeting the Prominin-2/BACH1 axis has also been shown to improve BMSC survival post-transplantation and mitigate IVDD progression by inhibiting ferroptosis. Our results support a new mechanistic insight into the regulation of the Prominin-2/BACH1/GLS pathway in BMSC ferroptosis. These finding could lead to potential therapeutic targets to improve the survival of engrafted BMSCs under oxidative stress circumstances.

Intervertebral disc degeneration is a leading cause of lower back pain and is characterized by pathological processes such as nucleus pulposus cell apoptosis, extracellular matrix imbalance, and annulus fibrosus rupture. These pathological changes result in disc height loss and functional decline, potentially leading to disc herniation. This comprehensive review aimed to address the current challenges in intervertebral disc degeneration treatment by evaluating the regenerative potential of stem cell-based therapies, with a particular focus on emerging technologies such as exosomes and gene vector systems. Through mechanisms such as differentiation, paracrine effects, and immunomodulation, stem cells facilitate extracellular matrix repair and reduce nucleus pulposus cell apoptosis. Despite recent advancements, clinical applications are hindered by challenges such as hypoxic disc environments and immune rejection. By analyzing recent preclinical and clinical findings, this review provided insights into optimizing stem cell therapy to overcome these obstacles and highlighted future directions in the field.

The efficacy of Bone Marrow Mesenchymal Stem Cell-derived Exosomes (BMSCs-Exo) in addressing the complexities of Polycystic Ovary Syndrome (PCOS) has been explored in a controlled experimental study using a DHEA-induced PCOS model in 6-8-week-old female NMRI mice. This research undertook an in vivo approach with fifteen female murine subjects to investigate the potential of BMSCs-Exo in promoting vascular regeneration and alleviating the adverse effects associated with PCOS. Through a strategic intervention, the study aimed to modulate the pathophysiological markers of oxidative stress and inflammation that are hallmark features of PCOS. Remarkably, the administration of BMSCs-Exo led to decreased CD31 expression in ovarian tissues, suggesting reduced angiogenesis and endothelial activation. Moreover, a significant reduction in pro-inflammatory cytokines and oxidative stress markers was noted, aligning closely with the metrics observed in the control group. These findings illuminate a promising therapeutic avenue utilizing BMSCs-Exo to recalibrate angiogenic, inflammatory, and oxidative stress responses in PCOS. This research not only contributes to the current understanding of PCOS management but also opens new doors for innovative clinical treatments.

Intervertebral disc degeneration (IVDD) is one of the most common musculoskeletal disorders in middle-aged and elderly people, and lower back pain (LBP) is the main clinical symptom [1, 2], which often causes significant pain and great economic burden to patients [3]. The current molecular mechanisms of IVDD include extracellular matrix degradation, cellular pyroptosis, apoptosis, necrotic apoptosis, senescence, and the newly discovered ferroptosis [4, 5], among which ferroptosis, as a new hot spot of research, has a non-negligible role in IVDD. Ferroptosis is an iron-dependent cell death caused by lipid peroxide accumulation [6]. Its main mechanism is cell death caused by lipid peroxidation by oxygen radicals due to iron overload and inhibition of pathways such as SLC7A11-GSH-GPX4. Currently, more and more studies have found a close relationship between IVDD and ferroptosis [7]. In the process of ferroptosis, the most important factors are abnormal iron metabolism, increased ROS, lipid peroxidation, and abnormal proteins such as GSH, GPX4, and system XC-. Our group has previously elucidated the pathogenesis of IVDD in terms of extracellular matrix degradation, myeloid cell senescence and pyroptosis, apoptosis, and inflammatory immunity. Therefore, this time, we will use ferroptosis as an entry point to discover the new mechanism of IVDD and provide guidance for clinical treatment.

This review highlights the key molecular and cellular mechanisms contributing to aging, such as DNA damage, mitochondrial dysfunction, telomere shortening, protein dysfunction, and defective autophagy. These biological mechanisms are involved in various oral health conditions prevalent in the elderly, including periodontal disease, oral cancer, xerostomia, dental caries, and temporomandibular joint disorders. Exosomes generated by mesenchymal stem cells possess substantial therapeutic potential. These exosomes are nanosized extracellular vesicles derived from cells and are involved in essential intercellular communication and tissue homeostasis. The exosome-based therapies proved superior to traditional cell-based approaches, due to lower immunogenicity, ease of storage, and avoidance of complications associated with cell transplantation. Furthermore, the diagnostic potential of exosomes as non-invasive biomarkers for aging processes and age-related oral diseases offers insights into disease diagnosis, staging, and monitoring. Among the challenges and future perspectives of translating exosome research from preclinical studies to clinical applications is the need for standardized procedures to fully harness the therapeutic and diagnostic capabilities of exosomes.

Intervertebral disc degeneration is the leading cause of low back pain, imposing significant burdens on patients, societies, and economies. Advancements in regenerative medicine have spotlighted extracellular vesicles as promising nanoparticles for intervertebral disc degeneration treatment. Extracellular vesicles retain the potential of cell therapy and serve as carriers to deliver their cargo to target cells, thereby regulating cell activity. This review summarizes the biogenesis and molecular composition of extracellular vesicles and explores their therapeutic roles in intervertebral disc degeneration treatment through various mechanisms. These mechanisms include mitigating cell loss and senescence, delaying extracellular matrix degeneration, and modulating the inflammatory microenvironment. Additionally, it highlights recent efforts in engineering extracellular vesicles to enhance their targeting and therapeutic efficacy. The integration of extracellular vesicle-based acellular therapy is anticipated to drive significant advancements in disc regenerative medicine.

Existing clinical treatment strategies often fail to effectively address the challenges associated with regenerating degenerated intervertebral discs. As a new regenerative medicine strategy, the extracellular vesicle strategy avoids the risks associated with cell transplantation and shows great promise in treating intervertebral disc degeneration by carrying therapeutic cargo. This review comprehensively examines the latest research, underlying mechanisms, and therapeutic potential of extracellular vesicles, offering a promising new strategy for intervertebral disc degeneration treatment.

Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain and significantly impacts quality of life. The pathogenesis of IVDD is largely driven by inflammation, pyroptosis, and extracellular matrix (ECM) degradation, which current therapies fail to adequately address. In this study, we explore the therapeutic potential of exosomes derived from endplate chondrocytes (EPCs), with a particular focus on the microRNA miR-128-3p. Our findings reveal that exosomes isolated from third-generation EPCs, enriched with miR-128-3p, exhibit potent anti-inflammatory and anti-pyroptotic effects in lipopolysaccharide-treated nucleus pulposus cells, which are key contributors to IVDD pathology. Specifically, we demonstrate that miR-128-3p delivered via EPC-derived exosomes directly targets TRAF6, effectively suppressing activation of the NF-κB signaling pathway, which is known to play a pivotal role in inflammation and ECM breakdown, leading to a marked reduction in pro-inflammatory cytokine release and mitigation of ECM degradation. Importantly, third-generation EPC exosomes, with higher levels of miR-128-3p, showed superior efficacy compared to fifth-generation EPCs, underscoring the critical role of miR-128-3p in mediating these protective effects. Our research highlights the promise of EPC-derived exosomes, particularly those rich in miR-128-3p, as a novel, cell-free therapeutic approach for IVDD. Unlike current treatments that focus primarily on symptom management, our approach targets key molecular pathways underlying IVDD progression, including inflammation, pyroptosis, and ECM degradation. By elucidating the miR-128-3p/TRAF6 axis, this study provides a foundation for the development of targeted, biologically based interventions aimed at halting or even reversing IVDD, thereby offering hope for more effective and lasting therapeutic options.

Acupuncture is an important therapy method in traditional Chinese medicine for treating intervertebral disc degeneration (IVDD), offering a wide range of applications. It is based on the theory of Chinese veterinary medicine and combines the stage of the disease course and individual differences for syndrome differentiation and treatment. However, there are few studies on the acupuncture treatment of cervical disc degeneration (CDD) in rabbits. Treatment based on syndrome differentiation is the basic principle of Chinese veterinary treatment. The selection of acupoints for external treatment should be based on individual etiology and pathogenesis. Nevertheless, most current studies do not follow this guideline. In this study, we established the CDD model and explored the mechanism of acupuncture treatment in alleviating CDD in rabbits by selecting a group of main acupoints including cervical Jiaji, Fengchi, Tianzhu, Naohu, Dazhui, and Houxi acupoints, combined with Western medicine's understanding of the pathogenesis of cervical spondylosis, from the anti-inflammatory, analgesic, and tissue-repairing perspectives. Magnetic resonance imaging (MRI) confirmed the successful establishment of the rabbit CDD model. Acupuncture stimulation reduced the increase of average and maximum neck temperature due to CDD in rabbits. The acupuncture treatment relieved the spinal disc damage in the neck of the rabbit, which also decreased the expression level of pro-apoptotic factor Bax and increased the expression level of anti-apoptotic factor Bcl-2. In addition, it can alleviate the abnormal apoptosis of rabbit intervertebral disc, decrease the expression level of inflammatory factors such as TNF-α, IL-1β, IL-2, and PGE2α, and alleviate the intense inflammation and pain response caused by CDD in rabbits. In conclusion, Acupuncture treatment can slow down the CDD of rabbits by regulating the inflammatory response and abnormal apoptosis of intervertebral disc tissue.

Intervertebral disc degeneration (IVDD) is widely recognized as one of the leading causes of low back pain. Intervertebral disc cells are the main components of the intervertebral disc (IVD), and their functions include synthesizing and secreting collagen and proteoglycans to maintain the structural and functional stability of the IVD. In addition, IVD cells are involved in several physiological processes. They help maintain nutrient metabolism balance in the IVD. They also have antioxidant and anti-inflammatory effects. Because of these roles, IVD cells are crucial in IVDD. When IVD cells are subjected to oxidative stress, mitochondria may become damaged, affecting normal cell function and accelerating degenerative changes. Mitochondria are the energy source of the cell and regulate important intracellular processes. As a key site for redox reactions, excessive oxidative stress and reactive oxygen species can damage mitochondria, leading to inflammation, DNA damage, and apoptosis, thus accelerating disc degeneration.

Describes the core knowledge of IVDD and oxidative stress. Comprehensively examines the complex relationship and potential mechanistic pathways between oxidative stress, mitochondrial dysfunction and IVDD. Highlights potential therapeutic targets and frontier therapeutic concepts. Draws researchers' attention and discussion on the future research of all three.

Origin, development and consequences of IVDD, molecular mechanisms of oxidative stress acting on mitochondria, mechanisms of oxidative stress damage to IVD cells, therapeutic potential of targeting mitochondria to alleviate oxidative stress in IVDD.

Targeted therapeutic strategies for oxidative stress and mitochondrial dysfunction are particularly critical in the treatment of IVDD. Using antioxidants and specific mitochondrial therapeutic agents can help reduce symptoms and pain. This approach is expected to significantly improve the quality of life for patients. Individualized therapeutic approaches, on the other hand, are based on an in-depth assessment of the patient's degree of oxidative stress and mitochondrial functional status to develop a targeted treatment plan for more precise and effective IVDD management. Additionally, we suggest preventive measures like customized lifestyle changes and medications. These are based on understanding how IVDD develops. The aim is to slow down the disease and reduce the chances of it coming back. Actively promoting clinical trials and evaluating the safety and efficacy of new therapies helps translate cutting-edge treatment concepts into clinical practice. These measures not only improve patient outcomes and quality of life but also reduce the consumption of healthcare resources and the socio-economic burden, thus having a positive impact on the advancement of the IVDD treatment field.

Discogenic low back pain (LBP) is a significant clinical condition arising from degeneration of the intervertebral disc, a common yet complex cause of chronic pain, defined by fissuring in the annulus fibrosus resulting in vascularization of growing granulation tissue and growth of nociceptive nerve fibers along the laceration area. This paper delves into the anatomical and pathophysiological underpinnings of discogenic LBP, emphasizing the role of intervertebral disc degeneration in the onset of pain. The pathogenesis is multifactorial, involving processes like mitochondrial dysfunction, accumulation of advanced glycation end products, and pyroptosis, all contributing to disc degeneration and subsequent pain. Despite its prevalence, diagnosing discogenic LBP is challenging due to the overlapping symptoms with other forms of LBP and the absence of definitive diagnostic criteria. Current diagnostic approaches include clinical evaluations, imaging techniques, and the exploration of potential biomarkers. Treatment strategies range from conservative management, such as physical therapy and pharmacological interventions, to more invasive procedures such as spinal injections and surgery. Emerging therapies targeting molecular pathways involved in disc degeneration are under investigation and hold potential for future clinical application. This paper highlights the necessity of a multidisciplinary approach combining clinical, imaging, and molecular data to enhance the accuracy of diagnosis and the effectiveness of treatment for discogenic LBP, ultimately aiming to improve patient outcomes.

Intervertebral disc degeneration (IDD) serves as the underlying pathology for various spinal degenerative conditions and is a primary contributor to low back pain (LBP). Recent studies have revealed a strong correlation between IDD and biological processes such as Programmed Cell Death (PCD), cellular senescence, inflammation, cell proliferation, extracellular matrix (ECM) degradation, and oxidative stress (OS). Of particular interest is the emerging evidence highlighting the significant involvement of the JNK signaling pathway in these fundamental biological processes of IDD. This paper explores the potential mechanisms through the JNK signaling pathway influences IDD in diverse ways. The objective of this article is to offer a fresh perspective and methodology for in-depth investigation into the pathogenesis of IDD by thoroughly examining the interplay between the JNK signaling pathway and IDD. Moreover, this paper summarizes the drugs and natural compounds that alleviate the progression of IDD by regulating the JNK signaling pathway. This paper aims to identify potential therapeutic targets and strategies for IDD treatment, providing valuable insights for clinical application.

Single-cell transcriptomics and high-throughput transcriptomics were used to screen factors significantly correlated with intervertebral disc degeneration (IDD). Expression changes of CFIm25 were determined via RT-qPCR and Western blot. NP cells were isolated from mouse intervertebral discs and induced to degrade with TNF-α and IL-1β. CFIm25 was knocked out using CRISPR-Cas9, and CFIm25 knockout and overexpressing nucleus pulposus (NP) cell lines were generated through lentiviral transfection. Proteoglycan expression, protein expression, inflammatory factor expression, cell viability, proliferation, migration, gene expression, and protein expression were analyzed using various assays (alcian blue staining, immunofluorescence, ELISA, CCK-8, EDU labeling, transwell migration, scratch assay, RT-qPCR, Western blot). The GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA was designed, and its effects on NP regeneration were assessed through in vitro and mouse model experiments. The progression of IDD in mice was evaluated using X-ray, H&E staining, and Safranin O-Fast Green staining. Immunohistochemistry was performed to determine protein expression in NP tissue. Proteomic analysis combined with in vitro and in vivo experiments was conducted to elucidate the mechanisms of hydrogel action.

CFIm25 was upregulated in IDD NP tissue and significantly correlated with disease progression. Inhibition of CFIm25 improved NP cell degeneration, enhanced cell proliferation, and migration. The hydrogel effectively knocked down CFIm25 expression, improved NP cell degeneration, promoted cell proliferation and migration, and mitigated IDD progression in a mouse model. The hydrogel inhibited inflammatory factor expression (IL-6, iNOS, IL-1β, TNF-α) by targeting the p38/NF-κB signaling pathway, increased collagen COLII and proteoglycan Aggrecan expression, and suppressed NP degeneration-related factors (COX-2, MMP-3).

The study highlighted the crucial role of CFIm25 in IDD and introduced a promising therapeutic strategy using a porous spherical GelMA-HAMA hydrogel loaded with APET×2 polypeptide and sgRNA. This innovative approach offers new possibilities for treating degenerated intervertebral discs.

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.

Characterized by their pivotal roles in cell-to-cell communication, cell proliferation, and immune regulation during tissue repair, exosomes have emerged as a promising avenue for "cell-free therapy" in clinical applications. Hydrogels, possessing commendable biocompatibility, degradability, adjustability, and physical properties akin to biological tissues, have also found extensive utility in tissue engineering and regenerative repair. The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process. This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin, bone, cartilage, nerves and tendons, with a focus on the methods for encapsulating and releasing exosomes within the hydrogels. It has also critically examined the gaps and limitations in current research, whilst proposed future directions and potential applications of this innovative approach.

Skeletal diseases impose a considerable burden on society. The clinical and tissue-engineering therapies applied to alleviate such diseases frequently result in complications and are inadequately effective. Research has shifted from conventional therapies based on mesenchymal stem cells (MSCs) to exosomes derived from MSCs. Exosomes are natural nanocarriers of endogenous DNA, RNA, proteins, and lipids and have a low immune clearance rate and good barrier penetration and allow targeted delivery of therapeutics. MSC-derived exosomes (MSC-exosomes) have the characteristics of both MSCs and exosomes, and so they can have both immunosuppressive and tissue-regenerative effects. Despite advances in our knowledge of MSC-exosomes, their regulatory mechanisms and functionalities are unclear. Here we review the therapeutic potential of MSC-exosomes for skeletal diseases.

Sphingosine 1-phosphate receptor 3 (S1PR3) participates in the inflammatory response in multiple types of diseases. However, the biological role of S1PR3 in intervertebral disc degeneration and the underlying mechanism are unclear. The aim of the present study was to investigate the functional role and the mechanism of S1PR3 in lipopolysaccharide (LPS)-induced human nucleus pulposus cells. The expression of S1PR3 and Toll-like receptor (TLR) 2 in LPS-induced nucleus pulposus (NP) cells was investigated using western blotting. The Cell Counting Kit-8 assay was used to detect cell proliferation, and the levels of inflammatory factors were detected using ELISA. Flow cytometry and western blotting were used for the assessment of apoptosis. The deposition of extracellular matrix (ECM) proteins was investigated using reverse transcription-quantitative PCR and western blotting. In addition, western blotting was used to investigate the protein expression levels of phosphorylated (p)-STAT3, STAT3, p-JNK, JNK, p-ERK, ERK, p-p38 and p38associated with STAT3 and MAPK signaling. S1PR3 expression was reduced, while TLR2 expression was elevated in LPS-induced human nucleus pulposus cells (HNPC). S1PR3 overexpression increased HNPC viability, inhibited the inflammatory response and suppressed apoptosis. Meanwhile, S1PR3 overexpression regulated the expression of ECM-related proteins. Additionally, overexpression of S1PR3 inhibited the expression of the TLR2-regulated STAT3 and MAPK pathways in LPS-induced HNPCs. Furthermore, TLR2 overexpression partially offset the impacts of S1PR3 overexpression on HNPC viability, apoptosis level, inflammation and as ECM degradation. In conclusion, STAT3 overexpression suppressed viability injury, the inflammatory response and the level of apoptosis and alleviated ECM protein deposition in HNPCs through the TLR2/STAT3 and TLR2/MAPK pathways, which may offer a promising candidate for the amelioration of intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a progressive degenerative disease influenced by various factors. Genkwanin, a known anti-inflammatory flavonoid, has not been explored for its potential in IVDD management. This study aims to investigate the effects and mechanisms of genkwanin on IVDD. In vitro, cell experiments revealed that genkwanin dose-dependently inhibited Interleukin-1β-induced expression levels of inflammatory factors (Interleukin-6, inducible nitric oxide synthase, cyclooxygenase-2) and degradation metabolic protein (matrix metalloproteinase-13). Concurrently, genkwanin upregulated the expression of synthetic metabolism genes (type II collagen, aggrecan). Moreover, genkwanin effectively reduced the phosphorylation of phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin, mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) pathways. Transcriptome sequencing analysis identified integrin α2 (ITGA2) as a potential target of genkwanin, and silencing ITGA2 reversed the activation of PI3K/AKT pathway induced by Interleukin-1β. Furthermore, genkwanin alleviated Interleukin-1β-induced senescence and apoptosis in nucleus pulposus cells. In vivo animal experiments demonstrated that genkwanin mitigated the progression of IVDD in the rat model through imaging and histological examinations. In conclusion, This study suggest that genkwanin inhibits inflammation in nucleus pulposus cells, promotes extracellular matrix remodeling, suppresses cellular senescence and apoptosis, through the ITGA2/PI3K/AKT, NF-κB and MAPK signaling pathways. These findings indicate that genkwanin may be a promising therapeutic candidate for IVDD.

As a major cause of low back pain, intervertebral disc degeneration is an increasingly prevalent chronic disease worldwide that leads to huge annual financial losses. The intervertebral disc consists of the inner nucleus pulposus, outer annulus fibrosus, and sandwiched cartilage endplates. All these factors collectively participate in maintaining the structure and physiological functions of the disc. During the unavoidable degeneration stage, the degenerated discs are surrounded by a harsh microenvironment characterized by acidic, oxidative, inflammatory, and chaotic cytokine expression. Loss of stem cell markers, imbalance of the extracellular matrix, increase in inflammation, sensory hyperinnervation, and vascularization have been considered as the reasons for the progression of intervertebral disc degeneration. The current treatment approaches include conservative therapy and surgery, both of which have drawbacks. Novel stimuli-responsive delivery systems are more promising future therapeutic options than traditional treatments. By combining bioactive agents with specially designed hydrogels, scaffolds, microspheres, and nanoparticles, novel stimuli-responsive delivery systems can realize the targeted and sustained release of drugs, which can both reduce systematic adverse effects and maximize therapeutic efficacy. Trigger factors are categorized into internal (pH, reactive oxygen species, enzymes, etc.) and external stimuli (photo, ultrasound, magnetic, etc.) based on their intrinsic properties. This review systematically summarizes novel stimuli-responsive delivery systems for intervertebral disc degeneration, shedding new light on intervertebral disc therapy.

Extracellular vesicles (EVs) derived from Mesenchymal Stromal Cells (MSCs) have shown promising therapeutic potential for multiple diseases, including intervertebral disc degeneration (IDD). Nevertheless, the limited production and unstable quality of EVs hindered the clinical application of EVs in IDD. Selenomethionine (Se-Met), the major form of organic selenium present in the cereal diet, showed various beneficial effects, including antioxidant, immunomodulatory and anti-apoptotic effects. In the current study, Se-Met was employed to treat MSCs to investigate whether Se-Met can facilitate the secretion of EVs by MSCs and optimize their therapeutic effects on IDD. On the one hand, Se-Met promoted the production of EVs by enhancing the autophagy activity of MSCs. On the other hand, Se-Met pretreated MSC-derived EVs (Se-EVs) exhibited an enhanced protective effects on alleviating nucleus pulposus cells (NPCs) senescence and attenuating IDD compared with EVs isolated from control MSCs (C-EVs) in vitro and in vivo. Moreover, we performed a miRNA microarray sequencing analysis on EVs to explore the potential mechanism of the protective effects of EVs. The result indicated that miR-125a-5p is markedly enriched in Se-EVs compared to C-EVs. Further in vitro and in vivo experiments revealed that knockdown of miR-125a-5p in Se-EVs (miRKD-Se-EVs) impeded the protective effects of Se-EVs, while overexpression of miR-125a-5p (miROE-Se-EVs) boosted the protective effects. In conclusion, Se-Met facilitated the MSC-derived EVs production and increased miR-125a-5p delivery in Se-EVs, thereby improving the protective effects of MSC-derived EVs on alleviating NPCs senescence and attenuating IDD.

Osteoporotic vertebral compression fractures (OVCFs) significantly increase morbidity and mortality, presenting a formidable challenge in healthcare. Traditional interventions such as vertebroplasty and kyphoplasty, despite their widespread use, are limited in addressing the secondary effects of vertebral fractures in adjacent areas and do not facilitate bone regeneration. This review paper explores the emerging domain of regenerative therapies, spotlighting stem cell therapy's transformative potential in OVCF treatment. It thoroughly describes the therapeutic possibilities and mechanisms of action of mesenchymal stem cells against OVCFs, relying on recent clinical trials and preclinical studies for efficacy assessment. Our findings reveal that stem cell therapy, particularly in combination with scaffolding materials, holds substantial promise for bone regeneration, spinal stability improvement, and pain mitigation. This integration of stem cell-based methods with conventional treatments may herald a new era in OVCF management, potentially improving patient outcomes. This review advocates for accelerated research and collaborative efforts to translate laboratory breakthroughs into clinical practice, emphasizing the revolutionary impact of regenerative therapies on OVCF management. In summary, this paper positions stem cell therapy at the forefront of innovation for OVCF treatment, stressing the importance of ongoing research and cross-disciplinary collaboration to unlock its full clinical potential.

Reactive oxygen species (ROS), predominantly generated by mitochondria, play a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Reduction of ROS levels may be an effective strategy to delay IVDD. In this study, we assessed whether umbilical cord mesenchymal stem cell-exosomes (UCMSC-exos) can be used to treat IVDD by suppressing ROS production caused by mitochondrial dysfunction.

Human UCMSC-exos were isolated and identified. Nucleus pulposus cells (NPCs) were stimulated with H2O2 in the presence or absence of exosomes. Then, 4D label free quantitative (4D-LFQ) proteomics were used to analyze the differentially expressed (DE) proteins. Mitochondrial membrane potential (MMP), mitochondrial ROS and protein levels were determined via immunofluorescence staining, flow cytometry and western blotting respectively. Additionally, high-throughput sequencing was performed to identify the DE miRNAs in NPCs. Finally, therapeutic effects of UCMSC-exos were investigated in a puncture-induced IVDD rat model. Degenerative grades of rat IVDs were assessed using magnetic resonance imaging and histochemical staining.

UCMSC-exos effectively improved the viability of NPCs and restored the expression of the extracellular matrix (ECM) proteins, collagen type II alpha-1 (COL2A1) and matrix metalloproteinase-13 induced by H2O2. Additionally, UCMSC-exos not only reduced the total intracellular ROS and mitochondrial superoxide levels, but also increased MMP in pathological NPCs. 4D-LFQ proteomics and western blotting further revealed that UCMSC-exos up-regulated the levels of the mitochondrial protein, mitochondrial transcription factor A (TFAM), in H2O2-induced NPCs. High-throughput sequencing and qRT-PCR uncovered that UCMSC-exos down-regulated the levels of miR-194-5p, a potential negative regulator of TFAM, induced by H2O2. Finally, in vivo results showed that UCMSC-exos injection improved the histopathological structure and enhanced the expression levels of COL2A1 and TFAM in the rat IVDD model.

Our findings suggest that UCMSC-exos promote ECM synthesis, relieve mitochondrial oxidative stress, and attenuate mitochondrial dysfunction in vitro and in vivo, thereby effectively treating IVDD.

This study provides solid experimental data support for the therapeutic effects of UCMSC-exos on IVDD, suggesting that UCMSC-exos will be a promising nanotherapy for IVDD.

Stem cells have shown tremendous potential and vast prospects in the research of intervertebral disc (IVD) regeneration and repair, attracting considerable attention in recent years. In this study, a bibliometric analysis and visualization techniques were employed to probe and analyze the hotspots and frontiers of stem cell research in IVD regeneration and repair, aiming to provide valuable references and insights for further investigations.

This study utilized the Science Citation Index Expanded from the Web of Science Core Collection database to retrieve and extract relevant literature records as research samples. Visual analysis tools such as VOSviewer 1.6.19, CiteSpace 6.2.R4, and bibliometric online analysis platforms were employed to construct scientific knowledge maps, providing a comprehensive and systematic exposition from various perspectives including collaboration networks, cocitation networks, and co-occurrence networks.

A total of 1075 relevant studies have been published in 303 journals by 4181 authors from 1198 institutions across 54 countries/regions. Over the past 20 years, the field of research has witnessed a significant growth in annual publications and citations. China and the United States have emerged as the primary participants and contributors, with the AO Research Institute Davos, Zhejiang University, and Tokai University being the top 3 leading research institutions. The most productive and highly cited author is Sakai D, who is regarded as a key leader in this research field. The journals with the highest number of publications and citations are Spine and Biomaterials, which are considered to be high-quality and authoritative core journals in this field. The current research focuses primarily on the sources and selection of stem cells, optimization of transplantation strategies, mechanisms of IVD regeneration, and the combined application of stem cells and biomaterials. However, there are still some challenges that need to be addressed, including posttransplantation stability, assessment of regenerative effects, and translation into clinical applications. Future research will concentrate on the diversity of stem cell sources, the application of novel biomaterials, personalized treatments, and the development of gene editing technologies, among other cutting-edge directions.

This study utilized bibliometric analysis and visualization techniques to unveil the hotspots and frontiers in the research on stem cells for IVD regeneration and repair. These research findings provide essential guidance and references for further experimental design and clinical applications. However, additional experiments and clinical studies are still needed to address the challenges and difficulties faced in the field of IVD regeneration and repair, thus offering novel strategies and approaches for the treatment of IVD diseases.

Stem cell therapy has gained attention in the field of regenerative medicine due to its potential to restore damaged tissue. This article focuses on the application of stem cell therapy for treating spinal pathologies, particularly intervertebral disc degeneration. Disc degeneration is a major cause of low back pain and is characterized by changes in the matrix and inflammation. Animal studies have demonstrated that the implantation of mesenchymal stem cells (MSCs) yields promising results, including increased disc height, improved hydration, and reduced inflammation. However, the number of clinical trials remains limited, necessitating further research to optimize MSCs therapy. Although preclinical studies offer valuable insights, caution is needed when extrapolating these findings to clinical practice. Stem cell therapy still faces multiple challenges, such as the durability and survival of MSCs upon implantation, uncertain pathways to discogenic differentiation, and the adverse impact of a harsh microenvironment on cell survival. The avascular nature of the intervertebral disc and dynamic loading conditions also affect the adaptation of transplanted cells. Despite these obstacles, stem cell therapy holds promise as a potential treatment for disc degeneration, and ongoing research aims to fill the current gap in conclusive data.

Intervertebral disc degeneration (IDD) is a disease that severely affects spinal health and is prevalent worldwide. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have regenerative potential and have emerged as promising therapeutic tools for treating degenerative discs. However, challenges such as the harsh microenvironment of degenerated intervertebral discs and EVs' limited stability and efficacy have hindered their clinical application. In recent years, hydrogels have attracted much attention in the field of IDD therapy because they can mimic the physiologic microenvironment of the disc and provide a potential solution by providing a suitable growth environment for MSCs and EVs. This review introduced the biological properties of MSCs and their derived EVs, summarized the research on the application of MSCs and EVs in IDD, summarized the current clinical trial studies of MSCs and EVs, and also explored the mechanism of action of MSCs and EVs in intervertebral discs. In addition, plenty of research elaborated on the mechanism of action of different classified hydrogels in tissue engineering, the synergistic effect of MSCs and EVs in promoting intervertebral disc regeneration, and their wide application in treating IDD. Finally, the challenges and problems still faced by hydrogel-loaded MSCs and EVs in the treatment of IDD are summarized, and potential solutions are proposed. This paper outlines the synergistic effects of MSCs and EVs in treating IDD in combination with hydrogels and aims to provide theoretical references for future related studies.

Intervertebral disc degeneration is the primary etiology of low back pain and radicular pain. This review examines the roles of crucial chemokines in different stages of degenerative disc disease, along with interventions targeting chemokine function to mitigate disc degeneration.

The release of chemokines from degenerated discs facilitates the infiltration and activation of immune cells, thereby intensifying the inflammatory cascade response. The migration of immune cells into the venous lumen is concomitant with the emergence of microvascular tissue and nerve fibers. Furthermore, the presence of neurogenic factors secreted by disc cells and immune cells stimulates the activation of pain-related cation channels in the dorsal root ganglion, potentially exacerbating discogenic and neurogenic pain and intensifying the degenerative cascade response mediated by chemokines. Gaining a deeper comprehension of the functions of chemokines and immune cells in these processes involving catabolism, angiogenesis, and injury detection could offer novel therapeutic avenues for managing symptomatic disc disease.

Chronic low back pain (LBP) is an increasingly prevalent issue, especially among aging populations. A major underlying cause of LBP is intervertebral disc degeneration (IDD), often triggered by intervertebral disc (IVD) inflammation. Inflammation of the IVD is divided into Septic and Aseptic inflammation. Conservative therapy and surgical treatment often fail to address the root cause of IDD. Recent advances in the treatment of IVD infection and inflammation range from antibiotics and small-molecule drugs to cellular therapies, biological agents, and innovative biomaterials. This review sheds light on the complex mechanisms of IVD inflammation and physiological and biochemical processes of IDD. Furthermore, it provides an overview of recent research developments in this area, intending to identify novel therapeutic targets and guide future clinical strategies for effectively treating IVD-related conditions.

Intervertebral disk (IVD) degeneration (IVDD) is a main factor in lower back pain, and immunomodulation plays a vital role in disease progression. The IVD is an immune privileged organ, and immunosuppressive molecules in tissues reduce immune cell (mainly monocytes/macrophages and mast cells) infiltration, and these cells can release proinflammatory cytokines and chemokines, disrupting the IVD microenvironment and leading to disease progression. Improving the inflammatory microenvironment in the IVD through immunomodulation during IVDD may be a promising therapeutic strategy. This article reviews the normal physiology of the IVD and its degenerative mechanisms, focusing on IVDD-related immunomodulation, including innate immune responses involving Toll-like receptors, NOD-like receptors and the complement system and adaptive immune responses that regulate cellular and humoral immunity, as well as IVDD-associated immunomodulatory therapies, which mainly include mesenchymal stem cell therapies, small molecule therapies, growth factor therapies, scaffolds, and gene therapy, to provide new strategies for the treatment of IVDD.

Intervertebral disc degeneration (IVDD) is the major cause of low-back pain. Histone deacetylase 9 (HDAC9) was dramatically decreased in the degenerative nucleus pulposus (NP) samples of patients with intervertebral disc degeneration (IVDD) according to bioinformatics analysis of Gene Expression Omnibus (GEO) GSE56081 dataset. This study aims to investigate the role of HDAC9 in IVDD progression.

The contribution of HDAC9 to the progression of IVDD was assessed using HDAC9 knockout (HDAC9KO) mice and NP-targeted HDAC9-overexpressing mice by IVD injection of adenovirus-mediated HDAC9 under a Col2a1 promoter. Magnetic resonance imaging (MRI) and histological analysis were used to examine the degeneration of IVD. NP cells were isolated from mice to investigate the effects of HDAC9 on apoptosis and viability. mRNA-seq and coimmunoprecipitation/mass spectrometry (co-IP/MS) analysis were used to analyze the HDAC9-regulated factors in the primary cultured NP cells.

HDAC9 was statistically decreased in the NP tissues in aged mice. HDAC9KO mice spontaneously developed age-related IVDD compared with wild-type (HDAC9WT) mice. In addition, overexpression of HDAC9 in NP cells alleviated IVDD symptoms in a surgically-induced IVDD mouse model. In an in vitro assay, knockdown of HDAC9 inhibited cell viability and promoted cell apoptosis of NP cells, and HDAC9 overexpression had the opposite effects in NP cells isolated from HDAC9KO mice. Results of mRNA-seq and co-IP/MS analysis revealed the possible proteins and signaling pathways regulated by HDAC9 in NP cells. RUNX family transcription factor 3 (RUNX3) was screened out for further study, and RUNX3 was found to be deacetylated and stabilized by HDAC9. Knockdown of RUNX3 restored the effects of HDAC9 silencing on NP cells by inhibiting apoptosis and increasing viability.

Our results suggest that HDAC9 plays an important role in the development and progression of IVDD. It might be required to protect NP cells against the loss of cell viability and apoptosis by inhibiting RUNX3 acetylation and expression during IVDD. Together, our findings suggest that HDAC9 may be a potential therapeutic target in IVDD.

Mesenchymal stem cells (MSCs) have great potential for the treatment of various immune diseases due to their unique immunomodulatory properties. However, MSCs exposed to the harsh inflammatory environment of damaged tissue after intravenous transplantation cannot exert their biological effects, and therefore, their therapeutic efficacy is reduced. In this challenging context, an in vitro preconditioning method is necessary for the development of MSC-based therapies with increased immunomodulatory capacity and transplantation efficacy.

To determine whether hypoxia and inflammatory factor preconditioning increases the immunosuppressive properties of MSCs without affecting their biological characteristics.

Umbilical cord MSCs (UC-MSCs) were pretreated with hypoxia (2% O2) exposure and inflammatory factors (interleukin-1β, tumor necrosis factor-α, interferon-γ) for 24 h. Flow cytometry, polymerase chain reaction, enzyme-linked immunosorbent assay and other experimental methods were used to evaluate the biological characteristics of pretreated UC-MSCs and to determine whether pretreatment affected the immunosuppressive ability of UC-MSCs in coculture with immune cells.

Pretreatment with hypoxia and inflammatory factors caused UC-MSCs to be elongated but did not affect their viability, proliferation or size. In addition, pretreatment significantly decreased the expression of coagulation-related tissue factors but did not affect the expression of other surface markers. Similarly, mitochondrial function and integrity were retained. Although pretreatment promoted UC-MSC apoptosis and senescence, it increased the expression of genes and proteins related to immune regulation. Pretreatment increased peripheral blood mononuclear cell and natural killer (NK) cell proliferation rates and inhibited NK cell-induced toxicity to varying degrees.

In summary, hypoxia and inflammatory factor preconditioning led to higher immunosuppressive effects of MSCs without damaging their biological characteristics.

To explore the mechanism of psoralen synergized with exosomes (exos)-loaded SPC25 on nucleus pulposus (NP) cell senescence in intervertebral disc degeneration (IVDD).

IVDD cellular models were established on NP cells by tert-butyl hydroperoxide (TBHP) induction, followed by the treatment of psoralen or/and exos from adipose-derived stem cells (ADSCs) transfected with SPC25 overexpression vector (ADSCs-oe-SPC25-Exos). The viability, cell cycle, apoptosis, and senescence of NP cells were examined, accompanied by the expression measurement of aggrecan, COL2A1, Bcl-2, Bax, CDK2, p16, and p21.

After TBHP-induced NP cells were treated with psoralen or ADSCs-oe-SPC25-Exos, cell proliferation and the expression of aggrecan, COL2A1, Bcl-2, and CDK2 were promoted; however, the expression of Bax, p16, p21, and inflammatory factors was decreased, and cell senescence, cycle arrest, and apoptosis were inhibited. Of note, psoralen combined with ADSCs-oe-SPC25-Exos further decelerated NP cell senescence and cycle arrest compared to psoralen or ADSCs-oe-SPC25-Exos alone.

Combined treatment of psoralen and ADSCs-oe-SPC25-Exos exerted an alleviating effect on NP cell senescence, which may provide an insightful idea for IVDD treatment.

Degenerative bone disorders such as intervertebral disc degeneration (IVDD), osteoarthritis (OA), and osteoporosis (OP) pose significant health challenges for aging populations and lack effective treatment options. The field of regenerative medicine holds promise in addressing these disorders, with a focus on utilizing extracellular vesicles (EVs) derived from stem cells as an innovative therapeutic approach. EVs have shown great potential in stimulating biological responses, making them an attractive candidate for rejuvenating degenerative bone disorders. However, a comprehensive review summarizing the current state of this field and providing a clear assessment of EV-based therapies in degenerative bone disorders is currently deficient. In this review, we aim to fill the existing gap by outlining the current knowledge on the role of EVs derived from different types of stem cells, such as mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells, in bone regeneration. Furthermore, we discuss the therapeutic potential of EV-based treatments for IVDD, OA, and OP. By substantiating the use of stem cell-derived EVs, we highlight their promising potential as a cell-free strategy to improve degenerative bone disorders.