A Hyaluronan and Platelet-Rich Plasma Hydrogel for Mesenchymal Stem Cell Delivery in the Intervertebral Disc: An Organ Culture Study

The purpose of the present pilot study was to evaluate the effect of a hydrogel composed of hyaluronic acid (HA) and platelet-rich plasma (PRP) as a carrier for human mesenchymal stem cells (hMSCs) for intervertebral disc (IVD) regeneration using a disc organ culture model. HA was mixed with batroxobin (BTX) and PRP to form a hydrogel encapsulating 1 × 10⁶ or 2 × 10⁶ hMSCs. Bovine IVDs were nucleotomized and filled with hMSCs suspended in ~200 μL of the PRP/HA/BTX hydrogel. IVDs collected at day 0 and nucleotomized IVDs with no hMSCs and/or hydrogel alone were used as controls. hMSCs encapsulated in the hydrogel were also cultured in well plates to evaluate the effect of the IVD environment on hMSCs. After 1 week, tissue structure, scaffold integration, hMSC viability and gene expression of matrix and nucleus pulposus (NP) cell markers were assessed. Histological analysis showed a better preservation of the viability of the IVD tissue adjacent to the gel in the presence of hMSCs (~70%) compared to the hydrogel without hMSCs. Furthermore, disc morphology was maintained, and the hydrogel showed signs of integration with the surrounding tissues. At the gene expression level, the hydrogel loaded with hMSCs preserved the normal metabolism of the tissue. The IVD environment promoted hMSC differentiation towards a NP cell phenotype by increasing cytokeratin-19 (KRT19) gene expression. This study demonstrated that the hydrogel composed of HA/PRP/BTX represents a valid carrier for hMSCs being able to maintain a good cell viability while stimulating cell activity and NP marker expression.     

A Single Injection of NTG-101 Reduces the Expression of Pain-Related Neurotrophins in a Canine Model of Degenerative Disc Disease

Background: Tissue sources of pain emanating from degenerative discs remains incompletely understood. Canine intervertebral discs (IVDs) were needle puncture injured, 4-weeks later injected with either phosphate-buffered saline (PBS) or NTG-101, harvested after an additional fourteen weeks and then histologically evaluated for the expression of NGFr, BDNF, TrkB and CALCRL proteins. Quantification was performed using the HALO automated cell-counting scoring platform. Immunohistochemical analysis was also performed on human IVD tissue samples obtained from spinal surgery. Immunohistochemical analysis and quantification of neurotrophins and neuropeptides was performed using an in vivo canine model of degenerative disc disease and human degenerative disc tissue sections. Discs injected with NTG-101 showed significantly lower levels of Nerve Growth Factor receptor (NGFr/TrkA, p = 0.0001), BDNF (p = 0.009), TrkB (p = 0.002) and CALCRL (p = 0.008) relative to PBS injections. Human IVD tissue obtained from spinal surgery due to painful DDD show robust expression of NGFr, BDNF, TrkB and CALCRL proteins. A single intradiscal injection of NTG-101 significantly inhibits the expression of NGFr, BDNF, TrkB and CALCRL proteins in degenerative canine IVDs. These results strongly suggest that NTG-101 inhibits the development of neurotrophins that are strongly associated with painful degenerative disc disease and may have profound effects upon the management of patients living with discogenic pain.     

The Cellular Composition of Bovine Coccygeal Intervertebral Discs: A Comprehensive Single-Cell RNAseq Analysis

Intervertebral disc (IVD) degeneration and its medical consequences is still one of the leading causes of morbidity worldwide. To support potential regenerative treatments for degenerated IVDs, we sought to deconvolute the cell composition of the nucleus pulposus (NP) and the annulus fibrosus (AF) of bovine intervertebral discs. Bovine calf tails have been extensively used in intervertebral disc research as a readily available source of NP and AF material from healthy and young IVDs. We used single-cell RNA sequencing (scRNAseq) coupled to bulk RNA sequencing (RNAseq) to unravel the cell populations in these two structures and analyze developmental changes across the rostrocaudal axis. By integrating the scRNAseq data with the bulk RNAseq data to stabilize the clustering results of our study, we identified 27 NP structure/tissue specific genes and 24 AF structure/tissue specific genes. From our scRNAseq results, we could deconvolute the heterogeneous cell populations in both the NP and the AF. In the NP, we detected a notochordal-like cell cluster and a progenitor stem cell cluster. In the AF, we detected a stem cell-like cluster, a cluster with a predominantly fibroblast-like phenotype and a potential endothelial progenitor cluster. Taken together, our results illustrate the cell phenotypic complexity of the AF and NP in the young bovine IVDs.     

Chondrogenic stimulation in mesenchymal stem cells using scaffold-based sustained release of platelet-rich plasma

Developing minimal invasive strategies via injectable hydrogels for effective repairing of cartilage defects is highly desired. Injectable hydrogels, which can simultaneously embed cell and growth factors (GFs), serve as in situ formed scaffolds and could support an accelerated tissue regeneration process. The purpose of this study is to fabricate a composite injectable hydrogel, based on alginate (Alg)/polyvinyl alcohol (PVA) incorporating platelet rich plasma (PRP)-encapsulated Alg sulfate (AlgS) microbeads, as a localized sustained release system of GFs, for the articular cartilage regeneration. The results show that synthesized AlgS microbeads support the sustained release of PRP GFs during 14 days, where preserve the bioactivity of them more than the free PRP. Rabbit adipose-derived mesenchymal stem cells in contact with PRP-loaded AlgS beads show more proliferation (2.7 folds) and have obviously higher deposition of collagen type ΙΙ and GAGs than free PRP treated ones. In addition, cells encapsulated into the hydrogel including PRP sustained release system show upregulated expression of collagen type ΙΙ (61 folds), Aggrecan (294 folds) and SOX9 (71.5 folds), as cartilage-critical genes, compared to the direct treatment by PRP. To summarize, the developed hybrid Alg/PVA hydrogel embedding with PRP-encapsulated AlgS microbeads is suggested as a potential in situ formed scaffold for cartilage regeneration.     

The Application of Mesenchymal Stromal Cells and Their Homing Capabilities to Regenerate the Intervertebral Disc

Chronic low back pain (LBP) remains a challenging condition to treat, and especially to cure. If conservative treatment approaches fail, the current “gold standard” for intervertebral disc degeneration (IDD)-provoked back pain is spinal fusion. However, due to its invasive and destructive nature, the focus of orthopedic research related to the intervertebral disc (IVD) has shifted more towards cell-based therapeutic approaches. They aim to reduce or even reverse the degenerative cascade by mimicking the human body’s physiological healing system. The implementation of progenitor and/or stem cells and, in particular, the delivery of mesenchymal stromal cells (MSCs) has revealed significant potential to cure the degenerated/injured IVD. Over the past decade, many research groups have invested efforts to find ways to utilize these cells as efficiently and sustainably as possible. This narrative literature review presents a summary of achievements made with the application of MSCs for the regeneration of the IVD in recent years, including their preclinical and clinical applications. Moreover, this review presents state-of-the-art strategies on how the homing capabilities of MSCs can be utilized to repair damaged or degenerated IVDs, as well as their current limitations and future perspectives.     

Importance of Matrix Cues on Intervertebral Disc Development,Degeneration, and Regeneration

Back pain is one of the leading causes of disability worldwide and is frequently caused by degeneration of the intervertebral discs. The discs’ development, homeostasis, and degeneration are driven by a complex series of biochemical and physical extracellular matrix cues produced by and transmitted to native cells. Thus, understanding the roles of different cues is essential for designing effective cellular and regenerative therapies. Omics technologies have helped identify many new matrix cues; however, comparatively few matrix molecules have thus far been incorporated into tissue engineered models. These include collagen type I and type II, laminins, glycosaminoglycans, and their biomimetic analogues. Modern biofabrication techniques, such as 3D bioprinting, are also enabling the spatial patterning of matrix molecules and growth factors to direct regional effects. These techniques should now be applied to biochemically, physically, and structurally relevant disc models incorporating disc and stem cells to investigate the drivers of healthy cell phenotype and differentiation. Such research will inform the development of efficacious regenerative therapies and improved clinical outcomes.     

Recent Advances in Managing Spinal Intervertebral Discs Degeneration

Low back pain (LBP) represents a frequent and debilitating condition affecting a large part of the global population and posing a worldwide health and economic burden. The major cause of LBP is intervertebral disc degeneration (IDD), a complex disease that can further aggravate and give rise to severe spine problems. As most of the current treatments for IDD either only alleviate the associated symptoms or expose patients to the risk of intraoperative and postoperative complications, there is a pressing need to develop better therapeutic strategies. In this respect, the present paper first describes the pathogenesis and etiology of IDD to set the framework for what has to be combated to restore the normal state of intervertebral discs (IVDs), then further elaborates on the recent advances in managing IDD. Specifically, there are reviewed bioactive compounds and growth factors that have shown promising potential against underlying factors of IDD, cell-based therapies for IVD regeneration, biomimetic artificial IVDs, and several other emerging IDD therapeutic options (e.g., exosomes, RNA approaches, and artificial intelligence).     

Evaluation of two chemical crosslinking methods of poly(vinyl alcohol) hydrogels for injectable nucleus pulposus replacement

Low back pain caused by intervertebral disc degeneration is one of the most common spinal disorders among patients seeking medical treatment. The most common surgical treatments are spinal fusion and total disc arthroplasty, both of which are very invasive surgical procedures. Nucleus pulposus replacement is an earlier stage intervention for disc degeneration. One of the material classes being studied for this application is hydrogels: a three‐dimensional hydrated network of polymer(s), which mimics the mechanical and physiological properties of the nucleus. Poly(vinyl alcohol) (PVA), poly(vinyl pyrrolidone) (PVP), and poly(ethylene glycol) (PEG) hydrogels have previously been shown to be great candidate materials for injectable nucleus pulposus replacement, but have experienced issues with swelling and mass retention. The addition of chemical crosslinking to the PVA/PVP/PEG hydrogel system will allow tailoring of the swelling, mechanical, injectability, and mass loss properties of the hydrogel network. Two chemical crosslinking methods were evaluated for the PVA/PVP/PEG hydrogel system by characterizing the hydrogels with compression, swelling, and spectroscopy experiments. The results of these experiments led to the selection of the difunctional crosslinking strategy using PEG functionalized with terminal epoxide group (PEG diglycidyl ether) as the preferred crosslinking method. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40843.     

Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?

Low back pain (LBP) has been among the leading causes of disability for the past 30 years. This highlights the need for improvement in LBP management. Many clinical trials focus on developing treatments against degenerative disc disease (DDD). The multifactorial etiology of DDD and associated risk factors lead to a heterogeneous patient population. It comes as no surprise that the outcomes of clinical trials on intradiscal mesenchymal stem cell (MSC) injections for patients with DDD are inconsistent. Intradiscal MSC injections have demonstrated substantial pain relief and significant disability-related improvements, yet they have failed to regenerate the intervertebral disc (IVD). Increasing evidence suggests that the positive outcomes in clinical trials might be attributed to the immunomodulatory potential of MSCs rather than to their regenerative properties. Therefore, patient stratification for inflammatory DDD phenotypes may (i) better serve the mechanisms of action of MSCs and (ii) increase the treatment effect. Modic type 1 changes—pathologic inflammatory, fibrotic changes in the vertebral bone marrow—are frequently observed adjacent to degenerated IVDs in chronic LBP patients and represent a clinically distinct subpopulation of patients with DDD. This review discusses whether degenerated IVDs of patients with Modic type 1 changes should be treated with an intradiscal MSC injection.     

Cell Therapy Using Bone Marrow-Derived Stem Cell Overexpressing BMP-7 for Degenerative Discs in a Rat Tail Disc Model

Degenerative discs can cause low back pain. Cell-based transplantation or growth factors therapy have been suggested as a strategy to stimulate disc regeneration. Bone marrow-derived mesenchymal stem cells (BMDMSC) containing bone morphogenetic protein-7 (BMP-7) gene were constructed. We evaluated the effectiveness of these BMP-7 overexpressing cells on degenerative discs in rat tails. In vitro and in vivo studies were designed. In the first stage, the rats were divided into two group according to discs punctured by different needle gauges (18 gauge and 22 gauge). In the second stage, the ideal size of needle was used to induce rat tail disc degeneration. These animals are divided into three groups according to timing of treatment (zero-week, two-week, four-week). Each group was divided into three treating subgroups: control group, BMDMSC group, and Baculo-BMP-7-BMDMSC group. Each rat undergoes radiography examination every two weeks. After eight weeks, the discs were histologically examined with hematoxylin and eosin stain and Alcian blue stain. The 18-gauge group exhibited significant decrease in disc height index (%) than 22-gauge group at eight weeks at both Co6-7 (58.1% ± 2.8% vs. 63.7% ± 1.0%, p = 0.020) and Co8-9 discs (62.7% ± 2.8% vs. 62.8% ± 1.5%, p = 0.010). Baculo-BMP-7-BMDMSCs group showed significant difference in disc height index compared to the BMDMSCs group at both Co6-7 (93.7% ± 1.5% vs. 84.8% ± 1.0%, p = 0.011) and Co8-9 (86.0% ± 2.1% vs. 81.8% ± 1.7%, p = 0.012). In Baculo-BMP-7-BMDMSCs group, the zero-week treatment subgroup showed significant better in disc height index compared to two-week treatment group (p = 0.044), and four-week treatment group (p = 0.011). The zero-week treatment subgroup in Baculo-BMP-7-BMDMSCs group also had significant lower histology score than two-week treatment (4.3 vs. 5.7, p = 0.045) and four-week treatment (4.3 vs. 6.0, p = 0.031). In conclusion, Baculo-BMP-7-BMDMSC can slow down the progression of disc degeneration, but could not provide evidence of regeneration. Early treatment might obtain more distinct results.     

Intervertebral Disc and Adipokine Leptin—Loves Me,Loves Me Not

Leptin—the most famous adipose tissue-secreted hormone—in the human body is mostly observed in a negative connotation, as the hormone level increases with the accumulation of body fat. Nowadays, fatness is becoming another normal body shape. Fatness is burdened with numerous illnesses—including low back pain and degenerative disease of lumbar intervertebral disc (IVD). IVD degeneration and IVD inflammation are two indiscerptible phenomena. Irrespective of the underlying pathophysiological background (trauma, obesity, nutrient deficiency), the inflammation is crucial in triggering IVD degeneration. Leptin is usually depicted as a proinflammatory adipokine. Many studies aimed at explaining the role of leptin in IVD degeneration, though mostly in in vitro and on animal models, confirmed leptin’s “bad reputation”. However, several studies found that leptin might have protective role in IVD metabolism. This review examines the current literature on the metabolic role of different depots of adipose tissue, with focus on leptin, in pathogenesis of IVD degeneration.     

The Proteolysis of ECM in Intervertebral Disc Degeneration

Intervertebral disc (IVD) degeneration (IDD) is a pathological process that commonly occurs throughout the human life span and is a major cause of lower back pain. Better elucidation of the molecular mechanisms involved in disc degeneration could provide a theoretical basis for the development of lumbar disc intervention strategies. In recent years, extracellular matrix (ECM) homeostasis has received much attention due to its relevance to the mechanical properties of IVDs. ECM proteolysis mediated by a variety of proteases is involved in the pathological process of disc degeneration. Here, we discuss in detail the relationship between the IVD as well as the ECM and the role of ECM proteolysis in the degenerative process of the IVD. Targeting ECM proteolysis-associated proteases may be an effective means of intervention in IDD.     

On-Growth and In-Growth Osseointegration Enhancement in PM Porous Ti-Scaffolds by Two Different Bioactivation Strategies: Alkali Thermochemical Treatment and RGD Peptide Coating

A lack of primary stability and osteointegration in metallic implants may result in implant loosening and failure. Adding porosity to metallic implants reduces the stress shielding effect and improves implant performance, allowing the surrounding bone tissue to grow into the scaffold. However, a bioactive surface is needed to stimulate implant osteointegration and improve mechanical stability. In this study, porous titanium implants were produced via powder sintering to create different porous diameters and open interconnectivity. Two strategies were used to generate a bioactive surface on the metallic foams: (1) an inorganic alkali thermochemical treatment, (2) grafting a cell adhesive tripeptide (RGD). RGD peptides exhibit an affinity for integrins expressed by osteoblasts, and have been reported to improve osteoblast adhesion, whereas the thermochemical treatment is known to improve titanium implant osseointegration upon implantation. Bioactivated scaffolds and control samples were implanted into the tibiae of rabbits to analyze the effect of these two strategies in vivo regarding bone tissue regeneration through interconnected porosity. Histomorphometric evaluation was performed at 4 and 12 weeks after implantation. Bone-to-implant contact (BIC) and bone in-growth and on-growth were evaluated in different regions of interest (ROIs) inside and outside the implant. The results of this study show that after a long-term postoperative period, the RGD-coated samples presented higher quantification values of quantified newly formed bone tissue in the implant’s outer area. However, the total analyzed bone in-growth was observed to be slightly greater in the scaffolds treated with alkali thermochemical treatment. These results suggest that both strategies contribute to enhancing porous metallic implant stability and osteointegration, and a combination of both strategies might be worth pursuing.     

Blocking the Function of Inflammatory Cytokines and Mediators by Using IL-10 and TGF-β: A Potential Biological Immunotherapy for Intervertebral Disc Degeneration in a Beagle Model

The debilitating effects of lower back pain are a major health issue worldwide. A variety of factors contribute to this, and oftentimes intervertebral disk degeneration (IDD) is an underlying cause of this disorder. Inflammation contributes to IDD, and inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, play key roles in the pathology of IDD. Therefore, the development of treatments that inhibit the expression and/or effects of TNF-α and IL-1β in IDD patients should be a promising therapeutic approach to consider. This study characterized the potential to suppress inflammatory cytokine production in degenerative intervertebral disc (NP) cells by treatment with IL-10 and TGF-β in a canine model of IDD. IDD was induced surgically in six male beagles, and degenerative NP cells were isolated and cultured for in vitro studies on cytokine production. Cultured degenerative NP cells were divided into four experimental treatment groups: untreated control, IL-10-treated, TGF-β-treated, and IL-10- plus TGF-β-treated cells. Cultured normal NP cells served as a control group. TNF-α expression was evaluated by fluorescence activated cell sorting (FACS) analysis and enzyme-linked immunosorbent assay (ELISA); moreover, ELISA and real-time PCR were also performed to evaluate the effect of IL-10 and TGF-β on NP cell cytokine expression in vitro. Our results demonstrated that IL-10 and TGF-β treatment suppressed the expression of IL-1β and TNF-α and inhibited the development of inflammatory responses. These data suggest that IL-10 and TGF-β should be evaluated as therapeutic approaches for the treatment of lower back pain mediated by IDD.     

miR-21 Promotes Human Nucleus Pulposus Cell Proliferation through PTEN/AKT Signaling

The precise role of nucleus pulposus cell proliferation in the pathogenesis of intervertebral disc degeneration remains to be elucidated. Recent findings have revealed that microRNAs, a class of small noncoding RNAs, may regulate cell proliferation in many pathological conditions. Here, we showed that miR-21 was significantly upregulated in degenerative nucleus pulposus tissues when compared with nucleus pulposus tissues that were isolated from patients with idiopathic scoliosis and that miR-10b levels were associated with disc degeneration grade. Moreover, bioinformatics target prediction identified PTEN as a putative target of miR-21. miR-21 inhibited PTEN expression by directly targeting the 3′UTR, and this inhibition was abolished through miR-21 binding site mutations. miR-21 overexpression stimulated cell proliferation and AKT signaling pathway activation, which led to cyclin D1 translation. Additionally, the increase in proliferation and cyclin D1 expression induced by miR-21 overexpression was almost completely blocked by {"type":"entrez-nucleotide","attrs":{"text":"Ly294002","term_id":"1257998346","term_text":"LY294002"}}Ly294002, an AKT inhibitor. Taken together, aberrant miR-21 upregulation in intervertebral disc degeneration could target PTEN, which would contribute to abnormal nucleus pulposus cell proliferation through derepressing the Akt pathway. Our study also underscores the potential of miR-21 and the PTEN/Akt pathway as novel therapeutic targets in intervertebral disc degeneration.     

In Situ Cell Signalling of the Hippo-YAP/TAZ Pathway in Reaction to Complex Dynamic Loading in an Intervertebral Disc Organ Culture

Recently, a dysregulation of the Hippo-YAP/TAZ pathway has been correlated with intervertebral disc (IVD) degeneration (IDD), as it plays a key role in cell survival, tissue regeneration, and mechanical stress. We aimed to investigate the influence of different mechanical loading regimes, i.e., under compression and torsion, on the induction and progression of IDD and its association with the Hippo-YAP/TAZ pathway. Therefore, bovine IVDs were assigned to one of four different static or complex dynamic loading regimes: (i) static, (ii) “low-stress”, (iii) “intermediate-stress”, and (iv) “high-stress” regime using a bioreactor. After one week of loading, a significant loss of relative IVD height was observed in the intermediate- and high-stress regimes. Furthermore, the high-stress regime showed a significantly lower cell viability and a significant decrease in glycosaminoglycan content in the tissue. Finally, the mechanosensitive gene CILP was significantly downregulated overall, and the Hippo-pathway gene MST1 was significantly upregulated in the high-stress regime. This study demonstrates that excessive torsion combined with compression leads to key features of IDD. However, the results indicated no clear correlation between the degree of IDD and a subsequent inactivation of the Hippo-YAP/TAZ pathway as a means of regenerating the IVD.     

Highly Organized Porous Gelatin-Based Scaffold by Microfluidic 3D-Foaming Technology and Dynamic Culture for Cartilage Tissue Engineering

A gelatin-based hydrogel scaffold with highly uniform pore size and biocompatibility was fabricated for cartilage tissue engineering using microfluidic 3D-foaming technology. Mainly, bubbles with different diameters, such as 100 μm and 160 μm, were produced by introducing an optimized nitrogen gas and gelatin solution at an optimized flow rate, and N₂/gelatin bubbles were formed. Furthermore, a cross-linking agent (1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide, EDC) was employed for the cross-linking reaction of the gelatin-based hydrogel scaffold with uniform bubbles, and then the interface between the close cells were broken by degassing. The pore uniformity of the gelatin-based hydrogel scaffolds was confirmed by use of a bright field microscope, conjugate focus microscope and scanning electron microscope. The in vitro degradation rate, mechanical properties, and swelling rate of gelatin-based hydrogel scaffolds with highly uniform pore size were studied. Rabbit knee cartilage was cultured, and its extracellular matrix content was analyzed. Histological analysis and immunofluorescence staining were employed to confirm the activity of the rabbit knee chondrocytes. The chondrocytes were seeded into the resulting 3D porous gelatin-based hydrogel scaffolds. The growth conditions of the chondrocyte culture on the resulting 3D porous gelatin-based hydrogel scaffolds were evaluated by MTT analysis, live/dead cell activity analysis, and extracellular matrix content analysis. Additionally, a dynamic culture of cartilage tissue was performed, and the expression of cartilage-specific proteins within the culture time was studied by immunofluorescence staining analysis. The gelatin-based hydrogel scaffold encouraged chondrocyte proliferation, promoting the expression of collagen type II, aggrecan, and sox9 while retaining the structural stability and durability of the cartilage after dynamic compression and promoting cartilage repair.     

The Regeneration of Large-Sized and Vascularized Adipose Tissue Using a Tailored Elastic Scaffold and dECM Hydrogels

A dome-shaped elastic poly(l-lactide-co-caprolactone) (PLCL) scaffold with a channel and pore structure was fabricated by a combinative method of 3D printing technology and the gel pressing method (13 mm in diameter and 6.5 mm in thickness) for patient-specific regeneration. The PLCL scaffold was combined with adipose decellularized extracellular matrix (adECM) and heart decellularized extracellular matrix (hdECM) hydrogels and human adipose-derived stem cells (hADSCs) to promote adipogenesis and angiogenesis. These scaffolds had mechanical properties similar to those of native adipose tissue for improved tissue regeneration. The results of the in vitro real-time PCR showed that the dECM hydrogel mixture induces adipogenesis. In addition, the in vivo study at 12 weeks demonstrated that the tissue-engineered PLCL scaffolds containing the hydrogel mixture (hdECM/adECM (80:20)) and hADSCs promoted angiogenesis and adipose tissue formation, and suppressed apoptosis. Therefore, we expect that our constructs will be clinically applicable as material for the regeneration of patient-specific large-sized adipose tissue.     

Current Status of the Instructional Cues Provided by Notochordal Cells in Novel Disc Repair Strategies

Numerous publications over the past 22 years, beginning with a seminal paper by Aguiar et al., have demonstrated the ability of notochordal cell-secreted factors to confer anabolic effects upon intervertebral disc (IVD) cells. Since this seminal paper, other scientific publications have demonstrated that notochordal cells secrete soluble factors that can induce anti-inflammatory, pro-anabolic and anti-cell death effects upon IVD nucleus pulposus (NP) cells in vitro and in vivo, direct human bone marrow-derived mesenchymal stem cells toward an IVD NP-like phenotype and repel neurite ingrowth. More recently these factors have been characterized, identified, and used therapeutically to induce repair upon injured IVDs in small and large pre-clinical animal models. Further, notochordal cell-rich IVD NPs maintain a stable, healthy extracellular matrix whereas notochordal cell-deficient IVDs result in a biomechanically and extracellular matrix defective phenotype. Collectively this accumulating body of evidence indicates that the notochordal cell, the cellular originator of the intervertebral disc holds vital instructional cues to establish, maintain and possibly regenerate the intervertebral disc.