Notochordal cell matrix: An inhibitor of neurite and blood vessel growth?

Vries, Stefan A.H. de; Doeselaar, Marina van; Meij, Björn P.; Tryfonidou, Marianna A.; Ito, Keita

doi:10.1002/jor.24114

Cited by 8 publications

(10 citation statements)

References 44 publications

(51 reference statements)

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“…The AF and EP are natural barriers resistant to vascular invasion due to intrinsic angiogenic inhibitors. IVD degeneration is often marked by blood vessel ingrowth, infiltration of inflammatory cells, and increased cell apoptosis (de Vries, van Doeselaar, Meij, Tryfonidou, & Ito, 2018;Freemont et al, 1997;McCann & Séguin, 2016;Phillips, Jordan-Mahy, Nicklin, & Le Maitre, 2013). For this reason, we then focused our investigation on the OAF zone in 6-month-old mice in order to reveal if Tnmd contributes to the maintenance of avascularity.…”

Section: Increased Angiogenesis Macrophages Infiltration and Apopmentioning

confidence: 99%

“…The IVD is the largest avascular tissue in the body and has poor self-healing potential (Huang, Urban, & Luk, 2014). Under pathological conditions, the IVDs express pro-angiogenic factors leading to neovascularization (Cornejo, Cho, Giannarelli, Iatridis, & Purmessur, 2015;de Vries, van Doeselaar, Meij, Tryfonidou, & Ito, 2018;Freemont et al, 1997;Purmessur, Freemont, & Hoyland, 2008). However, the impact of anti-angiogenic factors in the maintenance of IVD avascularity remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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The intervertebral disc (IVD) degeneration is thought to be closely related to ingrowth of new blood vessels. However, the impact of anti‐angiogenic factors in the maintenance of IVD avascularity remains unknown. Tenomodulin (Tnmd) is a tendon/ligament‐specific marker and anti‐angiogenic factor with abundant expression in the IVD. It is still unclear whether Tnmd contributes to the maintenance of IVD homeostasis, acting to inhibit vascular ingrowth into this normally avascular tissue. Herein, we investigated whether IVD degeneration could be induced spontaneously by the absence of Tnmd. Our results showed that Tnmd was expressed in an age‐dependent manner primarily in the outer annulus fibrous (OAF) and it was downregulated at 6 months of age corresponding to the early IVD degeneration stage in mice. Tnmd knockout (Tnmd−/−) mice exhibited more rapid progression of age‐related IVD degeneration. These signs include smaller collagen fibril diameter, markedly lower compressive stiffness, reduced multiple IVD‐ and tendon/ligament‐related gene expression, induced angiogenesis, and macrophage infiltration in OAF, as well as more hypertrophic‐like chondrocytes in the nucleus pulposus. In addition, Tnmd and chondromodulin I (Chm1, the only homologous gene to Tnmd) double knockout (Tnmd−/−Chm1−/−) mice displayed not only accelerated IVD degeneration, but also ectopic bone formation of IVD. Lastly, the absence of Tnmd in OAF‐derived cells promoted p65 and matrix metalloproteinases upregulation, and increased migratory capacity of human umbilical vein endothelial cells. In sum, our data provide clear evidences that Tnmd acts as an angiogenic inhibitor in the IVD homeostasis and protects against age‐related IVD degeneration. Targeting Tnmd may represent a novel therapeutic strategy for attenuating age‐related IVD degeneration.

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Section: Increased Angiogenesis Macrophages Infiltration and Apopmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

et al. 2020

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“… 3 We further elucidate the immune privilege of the disc, which is established by physical and molecular barriers, such as blood-NP barrier (BNB) and FasL. 4 Although the role of NCs or the NC-derived matrix in angiogenesis remains controversial, 20 studies have shown that NC-derived factors can inhibit angiogenic processes, indicating their potential role in inhibiting vascular in-growth treatment. 9 With the use of mass spectrometry, Matta et al.…”

Section: Discussionmentioning

confidence: 99%

Notochordal-Cell-Derived Exosomes Induced by Compressive Load Inhibit Angiogenesis via the miR-140-5p/Wnt/β-Catenin Axis

Sun

Liu

et al. 2020

Molecular Therapy - Nucleic Acids

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Angiogenesis is a pathological signature of intervertebral disc degeneration (IDD). Accumulating evidence has shown that notochordal cells (NCs) play an essential role in maintaining intervertebral disc development and homeostasis with inhibitive effect on blood vessel in-growth. However, the anti-angiogenesis mechanism of NCs is still unclear. In the current study, we, for the first time, isolated NC-derived exosomes (NC-exos) and showed their increased concentration following compressive load cultures. We further found that NC-exos from 0.5 MPa compressive load cultures (0.5 MPa/NC-exos) inhibit angiogenesis via transferring high expressed microRNA (miR)-140-5p to endothelial cells and regulating the downstream Wnt/β-catenin pathway. Clinical evidence showed that exosomal miR-140-5p expression of the nucleus pulposus is negatively correlated with angiogenesis in IDD. Finally, 0.5 MPa/NC-exos were demonstrated to have a therapeutical impact on the degenerated disc with an anti-angiogenesis effect in an IDD model. Consequently, our present findings provide insights into the anti-angiogenesis mechanism of NC-exos, indicating their therapeutic potential for IDD.

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“…Interestingly, NCM's anabolic effect on adult human NPCs was stronger compared with NCCM derived from the same porcine spines. In another in vitro study, however, 2 mg/ml NCM did not exert any anti-angiogenic and antineurogenic effects (de Vries et al, 2018b). Based on the overall promising anabolic in vitro benefits, the effect of 10 mg/ml NCM (concentration based on the dose-finding invitro pilot on canine NPCs) was tested in vivo on mildly (spontaneously) and moderately (induced) degenerated chondrodystrophic canine IVDs (Bach et al, 2018).…”

Section: Notochordal Cell-derived Ecm and Decellularized Np Tissuementioning

confidence: 99%

Notochordal Cell-Based Treatment Strategies and Their Potential in Intervertebral Disc Regeneration

Bach

Poramba‐Liyanage

Riemers

et al. 2022

Front. Cell Dev. Biol.

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Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD.

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Notochordal cell matrix: An inhibitor of neurite and blood vessel growth?

Cited by 8 publications

References 44 publications

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Loss of tenomodulin expression is a risk factor for age‐related intervertebral disc degeneration

Notochordal-Cell-Derived Exosomes Induced by Compressive Load Inhibit Angiogenesis via the miR-140-5p/Wnt/β-Catenin Axis

Notochordal Cell-Based Treatment Strategies and Their Potential in Intervertebral Disc Regeneration

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