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Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second...
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Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 30 August 2025 | Viewed by 5022

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 are remarkable trends 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 of the IVDs as a result of several factors, including injury, aging, apoptosis of the 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 for restoring degenerated IVDs using growth factor proteins to stimulate cell activity and increase extracellular matrix synthesis. Alternatively, to overcome the rapid biological clearance, some studies have demonstrated gene transfer into nucleus pulposus cells, which provides the continuous synthesis of therapeutic proteins. In addition, the 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 the degeneration and regeneration of IVDs for new treatment strategies. 

We look forward to your contributions.

Dr. Hideki Sudo
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • spine
  • intervertebral disc
  • biomaterial
  • stem cell
  • gene therapy

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Related Special Issue

Published Papers (3 papers)

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Research

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22 pages, 16663 KiB  
Article
Gene-Silencing Therapeutic Approaches Targeting PI3K/Akt/mTOR Signaling in Degenerative Intervertebral Disk Cells: An In Vitro Comparative Study Between RNA Interference and CRISPR–Cas9
by Masao Ryu, Takashi Yurube, Yoshiki Takeoka, Yutaro Kanda, Takeru Tsujimoto, Kunihiko Miyazaki, Hiroki Ohnishi, Tomoya Matsuo, Naotoshi Kumagai, Kohei Kuroshima, Yoshiaki Hiranaka, Ryosuke Kuroda and Kenichiro Kakutani
Cells 2024, 13(23), 2030; https://doi.org/10.3390/cells13232030 - 9 Dec 2024
Viewed by 1429
Abstract
The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR [...] Read more.
The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway is important in the intervertebral disk, which is the largest avascular, hypoxic, low-nutrient organ in the body. To examine gene-silencing therapeutic approaches targeting PI3K/Akt/mTOR signaling in degenerative disk cells, an in vitro comparative study was designed between small interfering RNA (siRNA)-mediated RNA interference (RNAi) and clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein 9 (Cas9) gene editing. Surgically obtained human disk nucleus pulposus cells were transfected with a siRNA or CRISPR–Cas9 plasmid targeting mTOR, RAPTOR, or RICTOR. Both of the approaches specifically suppressed target protein expression; however, the 24-h transfection efficiency differed by 53.8–60.3% for RNAi and 88.1–89.3% for CRISPR–Cas9 (p < 0.0001). Targeting mTOR, RAPTOR, and RICTOR all induced autophagy and inhibited apoptosis, senescence, pyroptosis, and matrix catabolism, with the most prominent effects observed with RAPTOR CRISPR–Cas9. In the time-course analysis, the 168-h suppression ratio of RAPTOR protein expression was 83.2% by CRISPR–Cas9 but only 8.8% by RNAi. While RNAi facilitates transient gene knockdown, CRISPR–Cas9 provides extensive gene knockout. Our findings suggest that RAPTOR/mTORC1 is a potential therapeutic target for degenerative disk disease. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition)
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13 pages, 2610 KiB  
Article
Bone Marrow Aspirate Concentrate Combined with Ultra-Purified Alginate Bioresorbable Gel Enhances Intervertebral Disc Repair in a Canine Model: A Preclinical Proof-of-Concept Study
by Daisuke Ukeba, Yoko Ishikawa, Katsuhisa Yamada, Takashi Ohnishi, Hiroyuki Tachi, Khin Khin Tha, Norimasa Iwasaki and Hideki Sudo
Cells 2024, 13(11), 987; https://doi.org/10.3390/cells13110987 - 5 Jun 2024
Cited by 1 | Viewed by 1531
Abstract
Although discectomy is commonly performed for lumbar intervertebral disc (IVD) herniation, the capacity for tissue repair after surgery is limited, resulting in residual lower back pain, recurrence of IVD herniation, and progression of IVD degeneration. Cell-based therapies, as one-step procedures, are desirable for [...] Read more.
Although discectomy is commonly performed for lumbar intervertebral disc (IVD) herniation, the capacity for tissue repair after surgery is limited, resulting in residual lower back pain, recurrence of IVD herniation, and progression of IVD degeneration. Cell-based therapies, as one-step procedures, are desirable for enhancing IVD repair. This study aimed to investigate the therapeutic efficacy of a combination of newly developed ultra-purified alginate (UPAL) gel and bone marrow aspirate concentrate (BMAC) implantation for IVD repair after discectomy. Prior to an in vivo study, the cell concentration abilities of three commercially available preparation kits for creating the BMAC were compared by measuring the number of bone marrow mesenchymal stem cells harvested from the bone marrow of rabbits. Subsequently, canine-derived BMAC was tested in a canine model using a kit which had the highest concentration rate. At 24 weeks after implantation, we evaluated the changes in the magnetic resonance imaging (MRI) signals as well as histological degeneration grade and immunohistochemical analysis results for type II and type I collagen-positive cells in the treated IVDs. In all quantitative evaluations, such as MRI and histological and immunohistochemical analyses of IVD degeneration, BMAC-UPAL implantation significantly suppressed the progression of IVD degeneration compared to discectomy and UPAL alone. This preclinical proof-of-concept study demonstrated the potential efficacy of BMAC-UPAL gel as a therapeutic strategy for implementation after discectomy, which was superior to UPAL and discectomy alone in terms of tissue repair and regenerative potential. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition)
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Review

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12 pages, 3039 KiB  
Review
Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics: Obstacles and Potential Breakthrough Technologies
by William Taylor and William Mark Erwin
Cells 2024, 13(24), 2103; https://doi.org/10.3390/cells13242103 - 19 Dec 2024
Viewed by 1523
Abstract
Pain and disability secondary to degenerative disc disease continue to burden the healthcare system, creating an urgent need for effective, disease-modifying therapies. Contemporary research has identified potential therapies that include protein-, cellular- and/or matrix-related approaches; however, none have yet achieved a meaningful clinical [...] Read more.
Pain and disability secondary to degenerative disc disease continue to burden the healthcare system, creating an urgent need for effective, disease-modifying therapies. Contemporary research has identified potential therapies that include protein-, cellular- and/or matrix-related approaches; however, none have yet achieved a meaningful clinical impact. The tissue-specific realities of the intervertebral disc create considerable therapeutic challenges due to the disc’s location, compartmentalization, hypovascularization and delicate physiological environment. Furthermore, the imaging modalities currently used in practice are largely unable to accurately identify sources of pain ostensibly discogenic in origin. These obstacles are considerable; however, recent research has begun to shed light on possible breakthrough technologies. Such breakthroughs include revolutionary imaging to better identify tissue sources of pain. Furthermore, novel molecular therapies have been shown to be able to mediate the progression of degenerative disc disease in some large animal studies, and even provide some insight into suppressing the development of tissue sources of discogenic pain. These potential breakthrough technologies have yet to be translated for clinical use. Full article
(This article belongs to the Special Issue Intervertebral Disc Degeneration and Regeneration: New Molecular Mechanisms and Therapeutics—Second Edition)
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