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Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics
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Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Tissues and Organs".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 15808

Special Issue Editor

Dr. Hideki Sudo

E-Mail Website
Guest Editor
Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido 060-0808, Japan
Interests: spine; intervertebral disc; biomaterial; stem cell; gene therapy; information technology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The increasing incidence of intervertebral disc (IVD) degeneration with age and its correlation with lower back pain, IVD herniation, and spinal canal stenosis is a remarkable trend in contemporary society. Although surgical treatments, such as discectomy and spinal fusion, are effective strategies, several complications have been reported, including reherniation and adjacent segment disease. These treatments do not focus on the etiology of IVD degeneration, which is poorly understood. Therefore, a novel and fundamental approach to treating IVD degeneration is highly anticipated. 

Dysfunction is caused by degeneration in the IVDs as a result of several factors, including injury, aging, apoptosis of nucleus pulposus, and mechanical overload, leading to diminished organization and repair of the extracellular matrix. 

Biological methods of IVD repair have gained interest as alternative options to restoring degenerated IVDs using growth factor proteins to stimulate cell activity and to increase extracellular matrix synthesis. Alternatively, to overcome the rapid biological clearance, some studies have demonstrated gene transfer into nucleus pulposus cells, which provides continuous synthesis of therapeutic proteins. In addition, injection of hydrogels or stem cells has been attempted in basic and translational research. 

This Special Issue aims to summarize the current knowledge on the molecular mechanisms of degeneration and regeneration of the IVD for new treatment strategies. 

We look forward to your contributions. 

Dr. Hideki Sudo
Guest Editor

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Related Special Issue

Published Papers (7 papers)

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Editorial

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2 pages, 151 KiB  
Editorial
Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics
by Hideki Sudo
Cells 2024, 13(2), 153; https://doi.org/10.3390/cells13020153 - 15 Jan 2024
Cited by 3 | Viewed by 1364
Abstract
The intervertebral disc (IVD) is a soft tissue that constitutes the spinal column together with the vertebrae, and consists of the central nucleus pulposus (gelatinous tissue) and the annulus fibrosus (rich in fibrous tissue) that surrounds the nucleus pulposus [...] Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)

Research

Jump to: Editorial, Review

34 pages, 15353 KiB  
Article
Inducing Angiogenesis in the Nucleus Pulposus
by Sheela R. Damle, Agata K. Krzyzanowska, Maximilian K. Korsun, Kyle W. Morse, Susannah Gilbert, Han Jo Kim, Oheneba Boachie-Adjei, Bernard A. Rawlins, Marjolein C. H. van der Meulen, Matthew B. Greenblatt, Chisa Hidaka and Matthew E. Cunningham
Cells 2023, 12(20), 2488; https://doi.org/10.3390/cells12202488 - 19 Oct 2023
Viewed by 1703
Abstract
Bone morphogenetic protein (BMP) gene delivery to Lewis rat lumbar intervertebral discs (IVDs) drives bone formation anterior and external to the IVD, suggesting the IVD is inhospitable to osteogenesis. This study was designed to determine if IVD destruction with a proteoglycanase, and/or generating [...] Read more.
Bone morphogenetic protein (BMP) gene delivery to Lewis rat lumbar intervertebral discs (IVDs) drives bone formation anterior and external to the IVD, suggesting the IVD is inhospitable to osteogenesis. This study was designed to determine if IVD destruction with a proteoglycanase, and/or generating an IVD blood supply by gene delivery of an angiogenic growth factor, could render the IVD permissive to intra-discal BMP-driven osteogenesis and fusion. Surgical intra-discal delivery of naïve or gene-programmed cells (BMP2/BMP7 co-expressing or VEGF165 expressing) +/- purified chondroitinase-ABC (chABC) in all permutations was performed between lumbar 4/5 and L5/6 vertebrae, and radiographic, histology, and biomechanics endpoints were collected. Follow-up anti-sFlt Western blotting was performed. BMP and VEGF/BMP treatments had the highest stiffness, bone production and fusion. Bone was induced anterior to the IVD, and was not intra-discal from any treatment. chABC impaired BMP-driven osteogenesis, decreased histological staining for IVD proteoglycans, and made the IVD permissive to angiogenesis. A soluble fragment of VEGF Receptor-1 (sFlt) was liberated from the IVD matrix by incubation with chABC, suggesting dysregulation of the sFlt matrix attachment is a possible mechanism for the chABC-mediated IVD angiogenesis we observed. Based on these results, the IVD can be manipulated to foster vascular invasion, and by extension, possibly osteogenesis. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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21 pages, 8745 KiB  
Article
Effects of Hyperbaric Oxygen Intervention on the Degenerated Intervertebral Disc: From Molecular Mechanisms to Animal Models
by Song-Shu Lin, Steve W. N. Ueng, Kowit-Yu Chong, Yi-Sheng Chan, Tsung-Ting Tsai, Li-Jen Yuan, Shih-Jung Liu, Chuen-Yung Yang, Hui-Yi Hsiao, Yi-Jen Hsueh, Chung-An Chen and Chi-Chien Niu
Cells 2023, 12(16), 2111; https://doi.org/10.3390/cells12162111 - 21 Aug 2023
Cited by 2 | Viewed by 1608
Abstract
MicroRNA (miRNA) 107 expression is downregulated but Wnt3a protein and β-catenin are upregulated in degenerated intervertebral disc (IVD). We investigated mir-107/Wnt3a-β-catenin signaling in vitro and in vivo following hyperbaric oxygen (HBO) intervention. Our results showed 96 miRNAs were upregulated and 66 downregulated in [...] Read more.
MicroRNA (miRNA) 107 expression is downregulated but Wnt3a protein and β-catenin are upregulated in degenerated intervertebral disc (IVD). We investigated mir-107/Wnt3a-β-catenin signaling in vitro and in vivo following hyperbaric oxygen (HBO) intervention. Our results showed 96 miRNAs were upregulated and 66 downregulated in degenerated nucleus pulposus cells (NPCs) following HBO treatment. The 3′ untranslated region (UTR) of the Wnt3a mRNA contained the “seed-matched-sequence” for miR-107. MiR-107 was upregulated and a marked suppression of Wnt3a was observed simultaneously in degenerated NPCs following HBO intervention. Knockdown of miR-107 upregulated Wnt3a expression in hyperoxic cells. HBO downregulated the protein expression of Wnt3a, phosphorylated LRP6, and cyclin D1. There was decreased TOP flash activity following HBO intervention, whereas the FOP flash activity was not affected. HBO decreased the nuclear translocation of β-catenin and decreased the secretion of MMP-3 and -9 in degenerated NPCs. Moreover, rabbit serum KS levels and the stained area for Wnt3a and β-catenin in repaired cartilage tended to be lower in the HBO group. We observed that HBO inhibits Wnt3a/β-catenin signaling-related pathways by upregulating miR-107 expression in degenerated NPCs. HBO may play a protective role against IVD degeneration and could be used as a future therapeutic treatment. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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15 pages, 3148 KiB  
Article
Injection of Ultra-Purified Stem Cells with Sodium Alginate Reduces Discogenic Pain in a Rat Model
by Hisataka Suzuki, Katsuro Ura, Daisuke Ukeba, Takashi Suyama, Norimasa Iwasaki, Masatoki Watanabe, Yumi Matsuzaki, Katsuhisa Yamada and Hideki Sudo
Cells 2023, 12(3), 505; https://doi.org/10.3390/cells12030505 - 3 Feb 2023
Cited by 7 | Viewed by 2485
Abstract
Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue [...] Read more.
Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue repair and reduces discogenic pain, and a combination of ultra-purified, Good Manufacturing Practice (GMP)-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs), and the UPAL gel increasingly enhanced IVD regeneration in animal models. This study investigated the therapeutic efficacy of injecting a mixture of REC and UPAL non-gelling solution for discogenic pain and IVD regeneration in a rat caudal nucleus pulposus punch model. REC and UPAL mixture and UPAL alone suppressed not only the expression of TNF-α, IL-6, and TrkA (p < 0.01, respectively), but also IVD degeneration and nociceptive behavior compared to punching alone (p < 0.01, respectively). Furthermore, REC and UPAL mixture suppressed these expression levels and nociceptive behavior compared to UPAL alone (p < 0.01, respectively). These results suggest that this minimally invasive treatment strategy with a single injection may be applied to treat discogenic pain and as a regenerative therapy. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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23 pages, 4334 KiB  
Article
In Vitro Characterization of a Tissue Renin-Angiotensin System in Human Nucleus Pulposus Cells
by Babak Saravi, Zhen Li, Valentina Basoli, Sibylle Grad, Sonja Häckel, Christoph E. Albers, Mauro Alini, Hagen Schmal, Peter Obid and Gernot Lang
Cells 2022, 11(21), 3418; https://doi.org/10.3390/cells11213418 - 28 Oct 2022
Cited by 1 | Viewed by 2125
Abstract
Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, [...] Read more.
Low back pain is a clinically highly relevant musculoskeletal burden and is associated with inflammatory as well as degenerative processes of the intervertebral disc. However, the pathophysiology and cellular pathways contributing to this devastating condition are still poorly understood. Based on previous evidence, we hypothesize that tissue renin-angiotensin system (tRAS) components, including the SARS-CoV-2 entry receptor angiotensin-converting enzyme 2 (ACE2), are present in human nucleus pulposus (NP) cells and associated with inflammatory and degenerative processes. Experiments were performed with NP cells from four human donors. The existence of angiotensin II, angiotensin II type 1 receptor (AGTR1), AGTR2, MAS-receptor (MasR), and ACE2 in human NP cells was validated with immunofluorescent staining and gene expression analysis. Hereafter, the cell viability was assessed after adding agonists and antagonists of the target receptors as well as angiotensin II in different concentrations for up to 48 h of exposure. A TNF-α-induced inflammatory in vitro model was employed to assess the impact of angiotensin II addition and the stimulation or inhibition of the tRAS receptors on inflammation, tissue remodeling, expression of tRAS markers, and the release of nitric oxide (NO) into the medium. Furthermore, protein levels of IL-6, IL-8, IL-10, and intracellular as well as secreted angiotensin II were assessed after exposing the cells to the substances, and inducible nitric oxide synthase (iNOS) levels were evaluated by utilizing Western blot. The existence of tRAS receptors and angiotensin II were validated in human NP cells. The addition of angiotensin II only showed a mild impact on gene expression markers. However, there was a significant increase in NO secreted by the cells. The gene expression ratios of pro-inflammatory/anti-inflammatory cytokines IL-6/IL-10, IL-8/IL-10, and TNF-α/IL-10 were positively correlated with the AGTR1/AGTR2 and AGTR1/MAS1 ratios, respectively. The stimulation of the AGTR2 MAS-receptor and the inhibition of the AGTR1 receptor revealed beneficial effects on the gene expression of inflammatory and tissue remodeling markers. This finding was also present at the protein level. The current data showed that tRAS components are expressed in human NP cells and are associated with inflammatory and degenerative processes. Further characterization of the associated pathways is warranted. The findings indicate that tRAS modulation might be a novel therapeutic approach to intervertebral disc disease. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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Review

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29 pages, 1570 KiB  
Review
A Review: Methodologies to Promote the Differentiation of Mesenchymal Stem Cells for the Regeneration of Intervertebral Disc Cells Following Intervertebral Disc Degeneration
by Takashi Ohnishi, Kentaro Homan, Akira Fukushima, Daisuke Ukeba, Norimasa Iwasaki and Hideki Sudo
Cells 2023, 12(17), 2161; https://doi.org/10.3390/cells12172161 - 28 Aug 2023
Cited by 9 | Viewed by 2153
Abstract
Intervertebral disc (IVD) degeneration (IDD), a highly prevalent pathological condition worldwide, is widely associated with back pain. Treatments available compensate for the impaired function of the degenerated IVD but typically have incomplete resolutions because of their adverse complications. Therefore, fundamental regenerative treatments need [...] Read more.
Intervertebral disc (IVD) degeneration (IDD), a highly prevalent pathological condition worldwide, is widely associated with back pain. Treatments available compensate for the impaired function of the degenerated IVD but typically have incomplete resolutions because of their adverse complications. Therefore, fundamental regenerative treatments need exploration. Mesenchymal stem cell (MSC) therapy has been recognized as a mainstream research objective by the World Health Organization and was consequently studied by various research groups. Implanted MSCs exert anti-inflammatory, anti-apoptotic, and anti-pyroptotic effects and promote extracellular component production, as well as differentiation into IVD cells themselves. Hence, the ultimate goal of MSC therapy is to recover IVD cells and consequently regenerate the extracellular matrix of degenerated IVDs. Notably, in addition to MSC implantation, healthy nucleus pulposus (NP) cells (NPCs) have been implanted to regenerate NP, which is currently undergoing clinical trials. NPC-derived exosomes have been investigated for their ability to differentiate MSCs from NPC-like phenotypes. A stable and economical source of IVD cells may include allogeneic MSCs from the cell bank for differentiation into IVD cells. Therefore, multiple alternative therapeutic options should be considered if a refined protocol for the differentiation of MSCs into IVD cells is established. In this study, we comprehensively reviewed the molecules, scaffolds, and environmental factors that facilitate the differentiation of MSCs into IVD cells for regenerative therapies for IDD. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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12 pages, 2168 KiB  
Review
Targeting Ferroptosis Holds Potential for Intervertebral Disc Degeneration Therapy
by Jiaxing Chen, Xinyu Yang, Yi Feng, Qiaochu Li, Jingjin Ma, Linbang Wang and Zhengxue Quan
Cells 2022, 11(21), 3508; https://doi.org/10.3390/cells11213508 - 5 Nov 2022
Cited by 16 | Viewed by 3383
Abstract
Intervertebral disc degeneration (IVDD) is a common pathological condition responsible for lower back pain, which can significantly increase economic and social burdens. Although considerable efforts have been made to identify potential mechanisms of disc degeneration, the treatment of IVDD is not satisfactory. Ferroptosis, [...] Read more.
Intervertebral disc degeneration (IVDD) is a common pathological condition responsible for lower back pain, which can significantly increase economic and social burdens. Although considerable efforts have been made to identify potential mechanisms of disc degeneration, the treatment of IVDD is not satisfactory. Ferroptosis, a recently reported form of regulated cell death (RCD), is characterized by iron-dependent lipid peroxidation and has been demonstrated to be responsible for a variety of degenerative diseases. Accumulating evidence suggests that ferroptosis is implicated in IVDD by decreasing viability and increasing extracellular matrix degradation of nucleus pulposus cells, annulus fibrosus cells, or endplate chondrocytes. In this review, we summarize the literature regarding ferroptosis of intervertebral disc cells and discuss its molecular pathways and biomarkers for treating IVDD. Importantly, ferroptosis is verified as a promising therapeutic target for IVDD. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics)
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