Getting to the Core: Exploring the Embryonic Development from Notochord to Nucleus Pulposus.

The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc's load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.

Enzymatic chemonucleolysis for lumbar disc herniation-an assessment of historical and contemporary efficacy and safety: a systematic review and meta-analysis.

Lumbar disc herniation (LDH) is often managed surgically. Enzymatic chemonucleolysis emerged as a non-surgical alternative. This systematic review and meta-analysis aims to assess the efficacy and safety of chemonucleolytic enzymes for LDH. The primary objective is to evaluate efficacy through "treatment success" (i.e., pain reduction) and severe adverse events (SAEs) rates. Additionally, differences in efficacy and safety trends among chemonucleolytic enzymes are explored. Following our PROSPERO registered protocol (CRD42023451546) and PRISMA guidelines, a systematic search of PubMed and Web of Science databases was conducted up to July 18, 2023. Inclusion criteria involved human LDH treatment with enzymatic chemonucleolysis reagents, assessing pain alleviation, imaging changes, and reporting on SAEs, with focus on allergic reactions. Quality assessment employed the Cochrane Source of Bias and MINORS tools. Meta-analysis utilized odds ratios (OR) with 95% confidence intervals (CI). Among 62 included studies (12,368 patients), chemonucleolysis demonstrated an 79% treatment success rate and significantly outperformed placebo controls (OR 3.35, 95% CI 2.41-4.65) and scored similar to surgical interventions (OR 0.65, 95% CI 0.20-2.10). SAEs occurred in 1.4% of cases, with slightly higher rates in chymopapain cohorts. No significant differences in "proceeding to surgery" rates were observed between chemonucleolysis and control cohorts. Limitations include dated and heterogeneous studies, emphasizing the need for higher-quality trials. Further optimization through careful patient selection and advances in therapy implementation may further enhance outcomes. The observed benefits call for wider clinical exploration and adoption. No funding was received for this review.

ISSLS PRIZE in Basic Science 2024: superiority of nucleus pulposus cell- versus mesenchymal stromal cell-derived extracellular vesicles in attenuating disc degeneration and alleviating pain.

PURPOSE: To investigate the therapeutic potential of extracellular vesicles (EVs) derived from human nucleus pulposus cells (NPCs), with a specific emphasis on Tie2-enhanced NPCs, compared to EVs derived from human bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a coccygeal intervertebral disc degeneration (IDD) rat model. METHODS: EVs were isolated from healthy human NPCs cultured under standard (NPCSTD-EVs) and Tie2-enhancing (NPCTie2+-EVs) conditions. EVs were characterized, and their potential was assessed in vitro on degenerative NPCs in terms of cell proliferation and senescence, with or without 10 ng/mL interleukin (IL)-1ß. Thereafter, 16 Sprague-Dawley rats underwent annular puncture of three contiguous coccygeal discs to develop IDD. Phosphate-buffered saline, NPCSTD-EVs, NPCTie2+-EVs, or BM-MSC-derived EVs were injected into injured discs, and animals were followed for 12 weeks until sacrifice. Behavioral tests, radiographic disc height index (DHI) measurements, evaluation of pain biomarkers, and histological analyses were performed to assess the outcomes of injected EVs. RESULTS: NPC-derived EVs exhibited the typical exosomal morphology and were efficiently internalized by degenerative NPCs, enhancing cell proliferation, and reducing senescence. In vivo, a single injection of NPC-derived EVs preserved DHI, attenuated degenerative changes, and notably reduced mechanical hypersensitivity. MSC-derived EVs showed marginal improvements over sham controls across all measured outcomes. CONCLUSION: Our results underscore the regenerative potential of young NPC-derived EVs, particularly NPCTie2+-EVs, surpassing MSC-derived counterparts. These findings raise questions about the validity of MSCs as both EV sources and cellular therapeutics against IDD. The study emphasizes the critical influence of cell type, source, and culture conditions in EV-based therapeutics.

Poly(ethylene Glycol) Methyl Ether Methacrylate-Based Injectable Hydrogels: Swelling, Rheological, and In Vitro Biocompatibility Properties with ATDC5 Chondrogenic Lineage.

Here, we present the synthesis of a series of chemical homopolymeric and copolymeric injectable hydrogels based on polyethylene glycol methyl ether methacrylate (PEGMEM) alone or with 2-dimethylamino ethyl methacrylate (DMAEM). The objective of this study was to investigate how the modification of hydrogel components influences the swelling, rheological attributes, and in vitro biocompatibility of the hydrogels. The hydrogels' networks were formed via free radical polymerization, as assured by 1H nuclear magnetic resonance spectroscopy (1H NMR). The swelling of the hydrogels directly correlated with the monomer and the catalyst amounts, in addition to the molecular weight of the monomer. Rheological analysis revealed that most of the synthesized hydrogels had viscoelastic and shear-thinning properties. The storage modulus and the viscosity increased by increasing the monomer and the crosslinker fraction but decreased by increasing the catalyst. MTT analysis showed no potential toxicity of the homopolymeric hydrogels, whereas the copolymeric hydrogels were toxic only at high DMEAM concentrations. The crosslinker polyethylene glycol dimethacrylate (PEGDMA) induced inflammation in ATDC5 cells, as detected by the significant increase in nitric oxide synthase type II activity. The results suggest a range of highly tunable homopolymeric and copolymeric hydrogels as candidates for cartilage regeneration.

Oleocanthal, an Antioxidant Phenolic Compound in Extra Virgin Olive Oil (EVOO): A Comprehensive Systematic Review of Its Potential in Inflammation and Cancer.

BACKGROUND: The Mediterranean diet is linked to various health benefits, especially the consumption of olive oil as a key component. Multiple studies highlight its advantages, particularly due to its fatty acid composition and additional components like phenolic compounds. A significant antioxidant compound, oleocanthal, known for its antioxidant properties, has gained attention in the pharmaceutical industry for its anti-inflammatory and antiproliferative effects. It shows promise in addressing cardiovascular diseases, metabolic syndrome, and neuroprotection. This systematic review aims to evaluate the existing literature on oleocanthal, examining its role in biological processes and potential impact on conditions like inflammation and cancer. METHODS: We performed several searches in PubMed (MEDLINE), Web of Science (WOS), and Cochrane based on the terms "Oleocanthal", "Cancer", and "Inflammation". The inclusion criteria were as follows: studies whose main topics were oleocanthal and cancer or inflammation. On the other hand, the exclusion criteria were studies that were not focused on oleocanthal, reviews, or editorial material. Given that these findings are explanatory rather than derived from clinical trials, we refrained from employing methods to assess potential bias. This systematic review did not receive any external funding. RESULTS: We found 174 records from these searches, where we discarded reviews and editorial material, duplicated articles, and 1 retracted article. Finally, we had 53 reports assessed for eligibility that were included in this review. DISCUSSION: OC exhibits promising therapeutic potential against both inflammation and cancer. We addressed its ability to target inflammatory genes and pathways, offering potential treatments for conditions like rheumatic diseases by regulating pathways such as NF-kB and MAPK. Additionally, OC's anticancer properties, particularly its notable inhibition of c-Met signaling across various cancers, highlight its efficacy, showcasing promise as a potential treatment.