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Regeneration for Spinal Diseases 2.0
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Regeneration for Spinal Diseases 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 48730

Special Issue Editors

Prof. Dr. Inbo Han

E-Mail Website
Guest Editor
Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Republic of Korea
Interests: spinal diseases (spinal cord injury, intervertebral disc degeneration, osteoporosis, etc.); pain; regeneration; stem cell; neuroprotection
Special Issues, Collections and Topics in MDPI journals
Dr. Takashi Yurube

E-Mail Website
Guest Editor
Department of Orthopaedic Surgery, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
Interests: minimally invasive reconstruction; spine surgery; regenerative medicine
Special Issues, Collections and Topics in MDPI journals
Dr. Daisuke Sakai

E-Mail Website
Guest Editor
Department Orthopaedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
Interests: intervertebral disc regeneration
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is my pleasure to inform you about the Special Issue “Regeneration for Spinal Disease”. Spinal diseases place a significant burden on the general population. The prevalence of degenerative spinal diseases, including intervertebral disc degeneration and osteoporosis, increases with age, and the affected population may suffer from long-term disability. The most serious conditions affecting the spine include spinal cord injury due to traumatic or non-traumatic causes (e.g., cancer, infection). Despite recent advancements in the management of these spinal diseases, there is growing research interest in discovering a novel therapeutic strategy.

This Special Issue focuses on regenerative therapy for spinal diseases, including spinal cord injury, intervertebral disc degeneration, osteoporosis, and pseudarthrosis. It will be published in the International Journal of Molecular Sciences (IJMS, ISSN 1422-0067), and is now open to receive submissions of full research articles and authoritative review papers for peer-review and possible publication.

Due to the success of the 1st edition, we would like to add more results and new insights from recent research projects. You can find the 1st edition at the following link.

https://www.mdpi.com/journal/ijms/special_issues/Spinal_Diseases

Prof. Dr. Inbo Han
Dr. Takashi Yurube
Dr. Daisuke Sakai
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • regeneration
  • intervertebral disc degeneration
  • spinal cord injury
  • osteoporosis
  • spinal fusion
  • muscle regeneration

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Published Papers (15 papers)

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Editorial

Jump to: Research, Review

5 pages, 205 KiB  
Editorial
Concepts of Regeneration for Spinal Diseases in 2022
by Takashi Yurube, Inbo Han and Daisuke Sakai
Int. J. Mol. Sci. 2022, 23(17), 9710; https://doi.org/10.3390/ijms23179710 - 26 Aug 2022
Cited by 3 | Viewed by 1154
Abstract
It is our pleasure to announce the publication of the Special Issue “Regeneration for Spinal Diseases 2 [...] Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)

Research

Jump to: Editorial, Review

20 pages, 6827 KiB  
Article
Synaptic Cell Adhesion Molecule 3 (SynCAM3) Deletion Promotes Recovery from Spinal Cord Injury by Limiting Glial Scar Formation
by Byeong Gwan Song, Su Yeon Kwon, Jae Won Kyung, Eun Ji Roh, Hyemin Choi, Chang Su Lim, Seong Bae An, Seil Sohn and Inbo Han
Int. J. Mol. Sci. 2022, 23(11), 6218; https://doi.org/10.3390/ijms23116218 - 1 Jun 2022
Cited by 4 | Viewed by 2752
Abstract
Synaptic cell adhesion molecules (SynCAMs) play an important role in the formation and maintenance of synapses and the regulation of synaptic plasticity. SynCAM3 is expressed in the synaptic cleft of the central nervous system (CNS) and is involved in the connection between axons [...] Read more.
Synaptic cell adhesion molecules (SynCAMs) play an important role in the formation and maintenance of synapses and the regulation of synaptic plasticity. SynCAM3 is expressed in the synaptic cleft of the central nervous system (CNS) and is involved in the connection between axons and astrocytes. We hypothesized that SynCAM3 may be related to the astrocytic scar (glial scar, the most important factor of CNS injury treatment) through extracellular matrix (ECM) reconstitution. Thus, we investigated the influence of the selective removal of SynCAM3 on the outcomes of spinal cord injury (SCI). SynCAM3 knock-out (KO) mice were subjected to moderate compression injury of the lower thoracic spinal cord using wild-type (WT) (C57BL/6JJc1) mice as controls. Single-cell RNA sequencing analysis over time, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and immunohistochemistry (IHC) showed reduced scar formation in SynCAM3 KO mice compared to WT mice. SynCAM3 KO mice showed improved functional recovery from SCI by preventing the transformation of reactive astrocytes into scar-forming astrocytes, resulting in improved ECM reconstitution at four weeks after injury. Our findings suggest that SynCAM3 could be a novel therapeutic target for SCI. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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16 pages, 8180 KiB  
Article
Association of Ligamentum Flavum Hypertrophy with Adolescent Idiopathic Scoliosis Progression—Comparative Microarray Gene Expression Analysis
by Shoji Seki, Mami Iwasaki, Hiroto Makino, Yasuhito Yahara, Miho Kondo, Katsuhiko Kamei, Hayato Futakawa, Makiko Nogami, Kenta Watanabe, Nguyen Tran Canh Tung, Tatsuro Hirokawa, Mamiko Tsuji and Yoshiharu Kawaguchi
Int. J. Mol. Sci. 2022, 23(9), 5038; https://doi.org/10.3390/ijms23095038 - 1 May 2022
Cited by 7 | Viewed by 2275
Abstract
The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides [...] Read more.
The role of the ligamentum flavum (LF) in the pathogenesis of adolescent idiopathic scoliosis (AIS) is not well understood. Using magnetic resonance imaging (MRI), we investigated the degrees of LF hypertrophy in 18 patients without scoliosis and on the convex and concave sides of the apex of the curvature in 22 patients with AIS. Next, gene expression was compared among neutral vertebral LF and LF on the convex and concave sides of the apex of the curvature in patients with AIS. Histological and microarray analyses of the LF were compared among neutral vertebrae (control) and the LF on the apex of the curvatures. The mean area of LF in the without scoliosis, apical concave, and convex with scoliosis groups was 10.5, 13.5, and 20.3 mm2, respectively. There were significant differences among the three groups (p < 0.05). Histological analysis showed that the ratio of fibers (Collagen/Elastic) was significantly increased on the convex side compared to the concave side (p < 0.05). Microarray analysis showed that ERC2 and MAFB showed significantly increased gene expression on the convex side compared with those of the concave side and the neutral vertebral LF cells. These genes were significantly associated with increased expression of collagen by LF cells (p < 0.05). LF hypertrophy was identified in scoliosis patients, and the convex side was significantly more hypertrophic than that of the concave side. ERC2 and MAFB genes were associated with LF hypertrophy in patients with AIS. These phenomena are likely to be associated with the progression of scoliosis. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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16 pages, 5000 KiB  
Article
Significant Therapeutic Effects of Adult Human Neural Stem Cells for Spinal Cord Injury Are Mediated by Monocyte Chemoattractant Protein-1 (MCP-1)
by Chung Kwon Kim, Jeong-Seob Won, Jae Yeol An, Ho Jin Lee, Ah-Jin Nam, Hyun Nam, Ji Yeoun Lee, Kyung-Hoon Lee, Sun-Ho Lee and Kyeung Min Joo
Int. J. Mol. Sci. 2022, 23(8), 4267; https://doi.org/10.3390/ijms23084267 - 12 Apr 2022
Cited by 3 | Viewed by 2316
Abstract
The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult [...] Read more.
The limited capability of regeneration in the human central nervous system leads to severe and permanent disabilities following spinal cord injury (SCI) while patients suffer from no viable treatment option. Adult human neural stem cells (ahNSCs) are unique cells derived from the adult human brain, which have the essential characteristics of NSCs. The objective of this study was to characterize the therapeutic effects of ahNSCs isolated from the temporal lobes of focal cortical dysplasia type IIIa for SCI and to elucidate their treatment mechanisms. Results showed that the recovery of motor functions was significantly improved in groups transplanted with ahNSCs, where, in damaged regions of spinal cords, the numbers of both spread and regenerated nerve fibers were observed to be higher than the vehicle group. In addition, the distance between neuronal nuclei in damaged spinal cord tissue was significantly closer in treatment groups than the vehicle group. Based on an immunohistochemistry analysis, those neuroprotective effects of ahNSCs in SCI were found to be mediated by inhibiting apoptosis of spinal cord neurons. Moreover, the analysis of the conditioned medium (CM) of ahNSCs revealed that such neuroprotective effects were mediated by paracrine effects with various types of cytokines released from ahNSCs, where monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) was identified as a key paracrine mediator. These results of ahNSCs could be utilized further in the preclinical and clinical development of effective and safe cell therapeutics for SCI, with no available therapeutic options at present. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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15 pages, 5419 KiB  
Article
Direct Reprogramming and Induction of Human Dermal Fibroblasts to Differentiate into iPS-Derived Nucleus Pulposus-like Cells in 3D Culture
by Shoji Seki, Mami Iwasaki, Hiroto Makino, Yasuhito Yahara, Yoshitaka Miyazaki, Katsuhiko Kamei, Hayato Futakawa, Makiko Nogami, Nguyen Tran Canh Tung, Tatsuro Hirokawa, Mamiko Tsuji and Yoshiharu Kawaguchi
Int. J. Mol. Sci. 2022, 23(7), 4059; https://doi.org/10.3390/ijms23074059 - 6 Apr 2022
Cited by 3 | Viewed by 2578
Abstract
Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may [...] Read more.
Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may therefore represent a candidate for the application of regenerative medicine, potentially employing normal human dermal fibroblasts (NHDFs) induced to differentiate into nucleus pulposus (NP) cells. Here, we used a three-dimensional culture system to demonstrate that ectopic expression of MYC, KLF4, NOTO, SOX5, SOX6, and SOX9 in NHDFs generated NP-like cells, detected using Safranin-O staining. Quantitative PCR, microarray analysis, and fluorescence-activated cell sorting revealed that the induced NP cells exhibited a fully differentiated phenotype. These findings may significantly contribute to the development of effective strategies for treating IVD diseases. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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13 pages, 3367 KiB  
Article
Ionizing Radiation Induces Disc Annulus Fibrosus Senescence and Matrix Catabolism via MMP-Mediated Pathways
by Jiongbiao Zhong, Joseph Chen, Anthony A. Oyekan, Michael W. Epperly, Joel S. Greenberger, Joon Y. Lee, Gwendolyn A. Sowa and Nam V. Vo
Int. J. Mol. Sci. 2022, 23(7), 4014; https://doi.org/10.3390/ijms23074014 - 5 Apr 2022
Cited by 8 | Viewed by 2525
Abstract
Previous research has identified an association between external radiation and disc degeneration, but the mechanism was poorly understood. This study explores the effects of ionizing radiation (IR) on inducing cellular senescence of annulus fibrosus (AF) in cell culture and in an in vivo [...] Read more.
Previous research has identified an association between external radiation and disc degeneration, but the mechanism was poorly understood. This study explores the effects of ionizing radiation (IR) on inducing cellular senescence of annulus fibrosus (AF) in cell culture and in an in vivo mouse model. Exposure of AF cell culture to 10–15 Gy IR for 5 min followed by 5 days of culture incubation resulted in almost complete senescence induction as evidenced by SA-βgal positive staining of cells and elevated mRNA expression of the p16 and p21 senescent markers. IR-induced senescent AF cells exhibited increased matrix catabolism, including elevated matrix metalloproteinase (MMP)-1 and -3 protein expression and aggrecanolysis. Analogous results were seen with whole body IR-exposed mice, demonstrating that genotoxic stress also drives disc cellular senescence and matrix catabolism in vivo. These results have important clinical implications in the potential adverse effects of ionizing radiation on spinal health. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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11 pages, 735 KiB  
Article
A High Body Mass Index and the Vacuum Phenomenon Upregulate Pain-Related Molecules in Human Degenerated Intervertebral Discs
by Masayuki Miyagi, Kentaro Uchida, Sho Inoue, Shotaro Takano, Mitsufumi Nakawaki, Ayumu Kawakubo, Hiroyuki Sekiguchi, Toshiyuki Nakazawa, Takayuki Imura, Wataru Saito, Eiki Shirasawa, Akiyoshi Kuroda, Shinsuke Ikeda, Yuji Yokozeki, Yusuke Mimura, Tsutomu Akazawa, Masashi Takaso and Gen Inoue
Int. J. Mol. Sci. 2022, 23(6), 2973; https://doi.org/10.3390/ijms23062973 - 10 Mar 2022
Cited by 4 | Viewed by 1975
Abstract
Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP’s pathomechanism. This study aimed to elucidate the relationships among the clinical findings, [...] Read more.
Animal studies suggest that pain-related-molecule upregulation in degenerated intervertebral discs (IVDs) potentially leads to low back pain (LBP). We hypothesized that IVD mechanical stress and axial loading contribute to discogenic LBP’s pathomechanism. This study aimed to elucidate the relationships among the clinical findings, radiographical findings, and pain-related-molecule expression in human degenerated IVDs. We harvested degenerated-IVD samples from 35 patients during spinal interbody fusion surgery. Pain-related molecules including tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6, calcitonin gene-related peptide (CGRP), microsomal prostaglandin E synthase-1 (mPGES1), and nerve growth factor (NGF) were determined. We also recorded preoperative clinical findings including body mass index (BMI), Oswestry Disability Index (ODI), and radiographical findings including the vacuum phenomenon (VP) and spinal instability. Furthermore, we compared pain-related-molecule expression between the VP (−) and (+) groups. BMI was significantly correlated with the ODI, CGRP, and mPGES-1 levels. In the VP (+) group, mPGES-1 levels were significantly higher than in the VP (−) group. Additionally, CGRP and mPGES-1 were significantly correlated. Axial loading and mechanical stress correlated with CGRP and mPGES-1 expression and not with inflammatory cytokine or NGF expression. Therefore, axial loading and mechanical stress upregulate CGRP and mPGES-1 in human degenerated IVDs, potentially leading to chronic discogenic LBP. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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12 pages, 2568 KiB  
Article
DUSP-1 Induced by PGE2 and PGE1 Attenuates IL-1β-Activated MAPK Signaling, Leading to Suppression of NGF Expression in Human Intervertebral Disc Cells
by Takuya Kusakabe, Yasunobu Sawaji, Kenji Endo, Hidekazu Suzuki, Takamitsu Konishi, Asato Maekawa, Kazuma Murata and Kengo Yamamoto
Int. J. Mol. Sci. 2022, 23(1), 371; https://doi.org/10.3390/ijms23010371 - 29 Dec 2021
Cited by 7 | Viewed by 1917
Abstract
The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory [...] Read more.
The molecular mechanism of discogenic low back pain (LBP) involves nonphysiological nerve invasion into a degenerated intervertebral disc (IVD), induced by nerve growth factor (NGF). Selective cyclooxygenase (COX)-2 inhibitors are mainly used in the treatment of LBP, and act by suppressing the inflammatory mediator prostaglandin E2 (PGE2), which is induced by inflammatory stimuli, such as interleukin-1β (IL-1β). However, in our previous in vitro study using cultured human IVD cells, we demonstrated that the induction of NGF by IL-1β is augmented by a selective COX-2 inhibitor, and that PGE2 and PGE1 suppress NGF expression. Therefore, in this study, to elucidate the mechanism of NGF suppression by PGE2 and PGE1, we focused on mitogen-activated protein kinases (MAPKs) and its phosphatase, dual-specificity phosphatase (DUSP)-1. IL-1β-induced NGF expression was altered in human IVD cells by MAPK pathway inhibitors. PGE2 and PGE1 enhanced IL-1β-induced DUSP-1 expression, and suppressed the phosphorylation of MAPKs in human IVD cells. In DUSP-1 knockdown cells established using small interfering RNA, IL-1β-induced phosphorylation of MAPKs was enhanced and prolonged, and NGF expression was significantly enhanced. These results suggest that PGE2 and PGE1 suppress IL-1β-induced NGF expression by suppression of the MAPK signaling pathway, accompanied by increased DUSP-1 expression. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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17 pages, 2098 KiB  
Article
In Situ Cell Signalling of the Hippo-YAP/TAZ Pathway in Reaction to Complex Dynamic Loading in an Intervertebral Disc Organ Culture
by Andreas S. Croft, Ysaline Roth, Katharina A. C. Oswald, Slavko Ćorluka, Paola Bermudez-Lekerika and Benjamin Gantenbein
Int. J. Mol. Sci. 2021, 22(24), 13641; https://doi.org/10.3390/ijms222413641 - 20 Dec 2021
Cited by 7 | Viewed by 2366
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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14 pages, 10082 KiB  
Article
Efficacy for Whitlockite for Augmenting Spinal Fusion
by Su Yeon Kwon, Jung Hee Shim, Yu Ha Kim, Chang Su Lim, Seong Bae An and Inbo Han
Int. J. Mol. Sci. 2021, 22(23), 12875; https://doi.org/10.3390/ijms222312875 - 28 Nov 2021
Cited by 4 | Viewed by 2045
Abstract
Whitlockite (WH) is the second most abundant inorganic component of human bone, accounting for approximately 25% of bone tissue. This study investigated the role of WH in bone remodeling and formation in a mouse spinal fusion model. Specifically, morphology and composition analysis, tests [...] Read more.
Whitlockite (WH) is the second most abundant inorganic component of human bone, accounting for approximately 25% of bone tissue. This study investigated the role of WH in bone remodeling and formation in a mouse spinal fusion model. Specifically, morphology and composition analysis, tests of porosity and surface area, thermogravimetric analysis, an ion-release test, and a cell viability test were conducted to analyze the properties of bone substitutes. The MagOss group received WH, Group A received 100% beta-tricalcium phosphate (β-TCP), Group B received 100% hydroxyapatite (HAp), Group C received 30% HAp/70% β-TCP, and Group D received 60% HAp/40% β-TCP (n = 10 each). All mice were sacrificed 6 weeks after implantation, and micro-CT, hematoxylin and eosin (HE) staining, and Masson trichome (MT) staining and immunohistochemistry were performed. The MagOss group showed more homogeneous and smaller grains, and nanopores (<500 nm) were found in only the MagOss group. On micro-CT, the MagOss group showed larger fusion mass and better graft incorporation into the decorticate mouse spine than other groups. In the in vivo experiment with HE staining, the MagOss group showed the highest new bone area (mean: decortication group, 9.50%; A, 15.08%; B, 15.70%; C, 14.76%; D, 14.70%; MagOss, 22.69%; p < 0.0001). In MT staining, the MagOss group demonstrated the highest new bone area (mean: decortication group, 15.62%; A, 21.41%; B, 22.86%; C, 23.07%; D, 22.47%; MagOss, 26.29%; p < 0.0001). In an immunohistochemical analysis for osteocalcin, osteopontin, and CD31, the MagOss group showed a higher positive area than other groups. WH showed comparable bone conductivity to HAp and β-TCP and increased new bone formation. WH is likely to be used as an improved bone substitute with better bone conductivity than HAp and β-TCP. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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14 pages, 2563 KiB  
Article
Activation of Hypoxia-Inducible Factor-1α Signaling Pathway Has the Protective Effect of Intervertebral Disc Degeneration
by Jin-Woo Kim, Hyun-Ju An, HyunJeong Yeo, Yunhui Jeong, HyeonHae Lee, Jusung Lee, Kisik Nam, Jongheon Lee, Dong-Eun Shin and Soonchul Lee
Int. J. Mol. Sci. 2021, 22(21), 11355; https://doi.org/10.3390/ijms222111355 - 21 Oct 2021
Cited by 16 | Viewed by 2322
Abstract
Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively [...] Read more.
Intervertebral discs (IVDs) have poor nutrient diffusion, because the nucleus pulposus (NP) lacks direct vascular supply and likely generates adenosine triphosphate by anaerobic glycolysis. Regulation of glycolysis is mediated by hypoxia-inducible factor-1α (HIF-1α), a transcription factor that responds to local oxygen tension. Constitutively active HIF-1α (CA HIF-1α) was created by point mutation and determined the protective role of HIF-1α in IVD degeneration. Under fluoroscopy, rat caudal IVD segments were stabbed by a needle puncture, and pcDNA3- HIF-1α wild-type (WT) or pcDNA3-CA HIF-1α was transfected into NP cell lines. The constitutive activity of CA HIF-1α was analyzed using a luciferase assay after cell lysis. Next, IVD tissue samples were retrieved from five patients with degenerative lumbar spinal stenosis at the time of surgery, and NP cells were cultured. NP cells were transfected with CA HIF-1α, and relevant gene expression was measured. HIF-1α protein levels in the nucleus were significantly higher, and transcriptional activity was 10.3-fold higher in NP cells with CA HIF-1α than in those with HIF-1α WT. Gene transfer of CA HIF-1α into NP cells enhanced the expression of Glut-1, Glut-3, aggrecan, type II collagen, and Sox9. Moreover, CA HIF-1α reduced the apoptosis of NP cells induced by the Fas ligand. The HIF-1α and collagen 2 expression levels were notably increased in the NP cells of the CA HIF-1α transfected segments in histology and immunohistochemistry study. Collectively, these results suggest that activation of HIF-1α signaling pathway may play a protective role against IVD degeneration and could be used as a future therapeutic agent. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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24 pages, 33070 KiB  
Article
Bazedoxifene, a Selective Estrogen Receptor Modulator, Promotes Functional Recovery in a Spinal Cord Injury Rat Model
by Yiyoung Kim, Eun Ji Roh, Hari Prasad Joshi, Hae Eun Shin, Hyemin Choi, Su Yeon Kwon, Seil Sohn and Inbo Han
Int. J. Mol. Sci. 2021, 22(20), 11012; https://doi.org/10.3390/ijms222011012 - 12 Oct 2021
Cited by 5 | Viewed by 3058
Abstract
In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal [...] Read more.
In research on various central nervous system injuries, bazedoxifene acetate (BZA) has shown two main effects: neuroprotection by suppressing the inflammatory response and remyelination by enhancing oligodendrocyte precursor cell differentiation and oligodendrocyte proliferation. We examined the effects of BZA in a rat spinal cord injury (SCI) model. Anti-inflammatory and anti-apoptotic effects were investigated in RAW 264.7 cells, and blood-spinal cord barrier (BSCB) permeability and angiogenesis were evaluated in a human brain endothelial cell line (hCMEC/D3). In vivo experiments were carried out on female Sprague Dawley rats subjected to moderate static compression SCI. The rats were intraperitoneally injected with either vehicle or BZA (1mg/kg pre-SCI and 3 mg/kg for 7 days post-SCI) daily. BZA decreased the lipopolysaccharide-induced production of proinflammatory cytokines and nitric oxide in RAW 264.7 cells and preserved BSCB disruption in hCMEC/D3 cells. In the rats, BZA reduced caspase-3 activity at 1 day post-injury (dpi) and suppressed phosphorylation of MAPK (p38 and ERK) at dpi 2, hence reducing the expression of IL-6, a proinflammatory cytokine. BZA also led to remyelination at dpi 20. BZA contributed to improvements in locomotor recovery after compressive SCI. This evidence suggests that BZA may have therapeutic potential to promote neuroprotection, remyelination, and functional outcomes following SCI. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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Review

Jump to: Editorial, Research

24 pages, 1099 KiB  
Review
Mesenchymal Stem Cell-Derived Exosomes and Intervertebral Disc Regeneration: Review
by Basanta Bhujel, Hae-Eun Shin, Dong-Jun Choi and Inbo Han
Int. J. Mol. Sci. 2022, 23(13), 7306; https://doi.org/10.3390/ijms23137306 - 30 Jun 2022
Cited by 29 | Viewed by 4652
Abstract
Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration [...] Read more.
Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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25 pages, 1779 KiB  
Review
Should Degenerated Intervertebral Discs of Patients with Modic Type 1 Changes Be Treated with Mesenchymal Stem Cells?
by Nick Herger, Paola Bermudez-Lekerika, Mazda Farshad, Christoph E. Albers, Oliver Distler, Benjamin Gantenbein and Stefan Dudli
Int. J. Mol. Sci. 2022, 23(5), 2721; https://doi.org/10.3390/ijms23052721 - 28 Feb 2022
Cited by 8 | Viewed by 10533
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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Review
Spheroid-Based Tissue Engineering Strategies for Regeneration of the Intervertebral Disc
by Jesil Kasamkattil, Anna Gryadunova, Ivan Martin, Andrea Barbero, Stefan Schären, Olga Krupkova and Arne Mehrkens
Int. J. Mol. Sci. 2022, 23(5), 2530; https://doi.org/10.3390/ijms23052530 - 25 Feb 2022
Cited by 13 | Viewed by 4899
Abstract
Degenerative disc disease, a painful pathology of the intervertebral disc (IVD), often causes disability and reduces quality of life. Although regenerative cell-based strategies have shown promise in clinical trials, none have been widely adopted clinically. Recent developments demonstrated that spheroid-based approaches might help [...] Read more.
Degenerative disc disease, a painful pathology of the intervertebral disc (IVD), often causes disability and reduces quality of life. Although regenerative cell-based strategies have shown promise in clinical trials, none have been widely adopted clinically. Recent developments demonstrated that spheroid-based approaches might help overcome challenges associated with cell-based IVD therapies. Spheroids are three-dimensional multicellular aggregates with architecture that enables the cells to differentiate and synthesize endogenous ECM, promotes cell-ECM interactions, enhances adhesion, and protects cells from harsh conditions. Spheroids could be applied in the IVD both in scaffold-free and scaffold-based configurations, possibly providing advantages over cell suspensions. This review highlights areas of future research in spheroid-based regeneration of nucleus pulposus (NP) and annulus fibrosus (AF). We also discuss cell sources and methods for spheroid fabrication and characterization, mechanisms related to spheroid fusion, as well as enhancement of spheroid performance in the context of the IVD microenvironment. Full article
(This article belongs to the Special Issue Regeneration for Spinal Diseases 2.0)
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