International Journal of Molecular Sciences

Editorial

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5 pages, 179 KiB

Open AccessEditorial

Concepts of Regeneration for Spinal Diseases in 2021

by Takashi Yurube, Inbo Han and Daisuke Sakai

Int. J. Mol. Sci. 2021, 22(16), 8356; https://doi.org/10.3390/ijms22168356 - 4 Aug 2021

Cited by 4 | Viewed by 2203

Abstract

It is our pleasure to announce the publication of the Special Issue “Regeneration for Spinal Diseases” in the International Journal of Molecular Sciences (IJMS, ISSN 1422-0067) [...] Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

Research

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17 pages, 3866 KiB

Open AccessArticle

Therapeutic Effect of BDNF-Overexpressing Human Neural Stem Cells (F3.BDNF) in a Contusion Model of Spinal Cord Injury in Rats

by Da-Jeong Chang, Hwi-Young Cho, Seyoung Hwang, Nayeon Lee, Chunggab Choi, Hyunseung Lee, Kwan Soo Hong, Seung-Hun Oh, Hyun Sook Kim, Dong Ah Shin, Young Wook Yoon and Jihwan Song

Int. J. Mol. Sci. 2021, 22(13), 6970; https://doi.org/10.3390/ijms22136970 - 28 Jun 2021

Cited by 19 | Viewed by 3827

Abstract

The most common type of spinal cord injury is the contusion of the spinal cord, which causes progressive secondary tissue degeneration. In this study, we applied genetically modified human neural stem cells overexpressing BDNF (brain-derived neurotrophic factor) (F3.BDNF) to determine whether they can [...] Read more.

The most common type of spinal cord injury is the contusion of the spinal cord, which causes progressive secondary tissue degeneration. In this study, we applied genetically modified human neural stem cells overexpressing BDNF (brain-derived neurotrophic factor) (F3.BDNF) to determine whether they can promote functional recovery in the spinal cord injury (SCI) model in rats. We transplanted F3.BDNF cells via intrathecal catheter delivery after a contusion of the thoracic spinal cord and found that they were migrated toward the injured spinal cord area by MR imaging. Transplanted F3.BDNF cells expressed neural lineage markers, such as NeuN, MBP, and GFAP and were functionally connected to the host neurons. The F3.BDNF-transplanted rats exhibited significantly improved locomotor functions compared with the sham group. This functional recovery was accompanied by an increased volume of spared myelination and decreased area of cystic cavity in the F3.BDNF group. We also observed that the F3.BDNF-transplanted rats showed reduced numbers of Iba1- and iNOS-positive inflammatory cells as well as GFAP-positive astrocytes. These results strongly suggest the transplantation of F3.BDNF cells can modulate inflammatory cells and glia activation and also improve the hyperalgesia following SCI. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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12 pages, 5512 KiB

Open AccessArticle

Augmented Chondroitin Sulfate Proteoglycan Has Therapeutic Potential for Intervertebral Disc Degeneration by Stimulating Anabolic Turnover in Bovine Nucleus Pulposus Cells under Changes in Hydrostatic Pressure

by Yoshiki Takeoka, Phani Paladugu, James D. Kang and Shuichi Mizuno

Int. J. Mol. Sci. 2021, 22(11), 6015; https://doi.org/10.3390/ijms22116015 - 2 Jun 2021

Cited by 6 | Viewed by 3038

Abstract

Nucleus pulposus (NP) cells are exposed to changes in hydrostatic pressure (HP) and osmotic pressure within the intervertebral disc. We focused on main disc matrix components, chondroitin sulfate proteoglycan (CSPG) and hyaluronan (HA) to elucidate the capability of augmented CSPG to enhance the [...] Read more.

Nucleus pulposus (NP) cells are exposed to changes in hydrostatic pressure (HP) and osmotic pressure within the intervertebral disc. We focused on main disc matrix components, chondroitin sulfate proteoglycan (CSPG) and hyaluronan (HA) to elucidate the capability of augmented CSPG to enhance the anabolism of bovine NP (bNP) cells under repetitive changes in HP at high osmolality. Aggrecan expression with CSPG in the absence of HP was significantly upregulated compared to the no-material control (phosphate buffer saline) under no HP at 3 days, and aggrecan expression with CSPG under HP was significantly higher than the control with HA under HP at 12 days. Collagen type I expression under no HP was significantly lower with CSPG than in controls at 3 days. Although matrix metalloproteinase 13 expression under HP was downregulated compared to no HP, it was significantly greater with HA than the control and CSPG, even under HP. Immunohistology revealed the involvement of mechanoreceptor of transient receptor potential vanilloid-4 activation under HP, suggesting an HP transduction mechanism. Addition of CSPG had anabolic and anti-fibrotic effects on bNP cells during the early culture period under no HP; furthermore, it showed synergy with dynamic HP to increase bNP-cell anabolism at later time points. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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15 pages, 36247 KiB

Open AccessArticle

Involvement of Autophagy in Rat Tail Static Compression-Induced Intervertebral Disc Degeneration and Notochordal Cell Disappearance

by Takashi Yurube, Hiroaki Hirata, Masaaki Ito, Yoshiki Terashima, Yuji Kakiuchi, Ryosuke Kuroda and Kenichiro Kakutani

Int. J. Mol. Sci. 2021, 22(11), 5648; https://doi.org/10.3390/ijms22115648 - 26 May 2021

Cited by 17 | Viewed by 3312

Abstract

The intervertebral disc is the largest avascular low-nutrient organ in the body. Thus, resident cells may utilize autophagy, a stress-response survival mechanism, by self-digesting and recycling damaged components. Our objective was to elucidate the involvement of autophagy in rat experimental disc degeneration. In [...] Read more.

The intervertebral disc is the largest avascular low-nutrient organ in the body. Thus, resident cells may utilize autophagy, a stress-response survival mechanism, by self-digesting and recycling damaged components. Our objective was to elucidate the involvement of autophagy in rat experimental disc degeneration. In vitro, the comparison between human and rat disc nucleus pulposus (NP) and annulus fibrosus (AF) cells found increased autophagic flux under serum deprivation rather in humans than in rats and in NP cells than in AF cells of rats (n = 6). In vivo, time-course Western blotting showed more distinct basal autophagy in rat tail disc NP tissues than in AF tissues; however, both decreased under sustained static compression (n = 24). Then, immunohistochemistry displayed abundant autophagy-related protein expression in large vacuolated disc NP notochordal cells of sham rats. Under temporary static compression (n = 18), multi-color immunofluorescence further identified rapidly decreased brachyury-positive notochordal cells with robust expression of autophagic microtubule-associated protein 1 light chain 3 (LC3) and transiently increased brachyury-negative non-notochordal cells with weaker LC3 expression. Notably, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic death was predominant in brachyury-negative non-notochordal cells. Based on the observed notochordal cell autophagy impairment and non-notochordal cell apoptosis induction under unphysiological mechanical loading, further investigation is warranted to clarify possible autophagy-induced protection against notochordal cell disappearance, the earliest sign of disc degeneration, through limiting apoptosis. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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25 pages, 17773 KiB

Open AccessArticle

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

by Martina Calió, Benjamin Gantenbein, Marcel Egli, Lucy Poveda and Fabian Ille

Int. J. Mol. Sci. 2021, 22(9), 4917; https://doi.org/10.3390/ijms22094917 - 6 May 2021

Cited by 23 | Viewed by 4064

Abstract

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) [...] Read more.

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. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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15 pages, 2463 KiB

Open AccessArticle

Effect of Whole Tissue Culture and Basic Fibroblast Growth Factor on Maintenance of Tie2 Molecule Expression in Human Nucleus Pulposus Cells

by Kosuke Sako, Daisuke Sakai, Yoshihiko Nakamura, Jordy Schol, Erika Matsushita, Takayuki Warita, Natsumi Horikita, Masato Sato and Masahiko Watanabe

Int. J. Mol. Sci. 2021, 22(9), 4723; https://doi.org/10.3390/ijms22094723 - 29 Apr 2021

Cited by 17 | Viewed by 2935

Abstract

Previous work showed a link between Tie2⁺ nucleus pulposus progenitor cells (NPPC) and disc degeneration. However, NPPC remain difficult to maintain in culture. Here, we report whole tissue culture (WTC) combined with fibroblast growth factor 2 (FGF2) and chimeric FGF (cFGF) supplementation [...] Read more.

Previous work showed a link between Tie2⁺ nucleus pulposus progenitor cells (NPPC) and disc degeneration. However, NPPC remain difficult to maintain in culture. Here, we report whole tissue culture (WTC) combined with fibroblast growth factor 2 (FGF2) and chimeric FGF (cFGF) supplementation to support and enhance NPPC and Tie2 expression. We also examined the role of PI3K/Akt and MEK/ERK pathways in FGF2 and cFGF-induced Tie2 expression. Young herniating nucleus pulposus tissue was used. We compared WTC and standard primary cell culture, with or without 10 ng/mL FGF2. PI3K/Akt and MEK/ERK signaling pathways were examined through western blotting. Using WTC and primary cell culture, Tie2 positivity rates were 7.0 ± 2.6% and 1.9 ± 0.3% (p = 0.004), respectively. Addition of FGF2 in WTC increased Tie2 positivity rates to 14.2 ± 5.4% (p = 0.01). FGF2-stimulated expression of Tie2 was reduced 3-fold with the addition of the MEK inhibitor PD98059 (p = 0.01). However, the addition of 1 μM Akt inhibitor, 124015-1MGCN, only reduced small Tie2 expression (p = 0.42). cFGF similarly increased the Tie2 expression, but did not result in significant phosphorylation in both the MEK/ERK and PI3K/Akt pathways. WTC with FGF2 addition significantly increased Tie2 maintenance of human NPPC. Moreover, FGF2 supports Tie2 expression via MEK/ERK and PI3K/Akt signals. These findings offer promising tools and insights for the development of NPPC-based therapeutics. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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14 pages, 3614 KiB

Open AccessArticle

Intervertebral Disc Regeneration Injection of a Cell-Loaded Collagen Hydrogel in a Sheep Model

by Andrea Friedmann, Andre Baertel, Christine Schmitt, Christopher Ludtka, Javorina Milosevic, Hans-Joerg Meisel, Felix Goehre and Stefan Schwan

Int. J. Mol. Sci. 2021, 22(8), 4248; https://doi.org/10.3390/ijms22084248 - 19 Apr 2021

Cited by 21 | Viewed by 3528

Abstract

Degenerated intervertebral discs (IVDs) were treated with autologous adipose-derived stem cells (ASC) loaded into an injectable collagen scaffold in a sheep model to investigate the implant’s therapeutic potential regarding the progression of degeneration of previously damaged discs. In this study, 18 merino sheep [...] Read more.

Degenerated intervertebral discs (IVDs) were treated with autologous adipose-derived stem cells (ASC) loaded into an injectable collagen scaffold in a sheep model to investigate the implant’s therapeutic potential regarding the progression of degeneration of previously damaged discs. In this study, 18 merino sheep were subjected to a 3-step minimally invasive injury and treatment model, which consisted of surgically induced disc degeneration, treatment of IVDs with an ASC-loaded collagen hydrogel 6 weeks post-operatively, and assessment of the implant’s influence on degenerative tissue changes after 6 and 12 months of grazing. Autologous ASCs were extracted from subcutaneous adipose tissue and cultivated in vitro. At the end of the experiment, disc heights were determined by µ-CT measurements and morphological tissue changes were histologically examined.Histological investigations show that, after treatment with the ASC-loaded collagen hydrogel implant, degeneration-specific features were observed less frequently. Quantitative studies of the degree of degeneration did not demonstrate a significant influence on potential tissue regeneration with treatment. Regarding disc height analysis, at both 6 and 12 months after treatment with the ASC-loaded collagen hydrogel implant a stabilization of the disc height can be seen. A complete restoration of the intervertebral disc heights however could not be achieved.The reported injection procedure describes in a preclinical model a translational therapeutic approach for degenerative disc diseases based on adipose-derived stem cells in a collagen hydrogel scaffold. Further investigations are planned with the use of a different injectable scaffold material using the same test model. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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21 pages, 17409 KiB

Open AccessArticle

Peripheral Nerve-Derived Stem Cell Spheroids Induce Functional Recovery and Repair after Spinal Cord Injury in Rodents

by Hye-Lan Lee, Chung-Eun Yeum, HyeYeong Lee, Jinsoo Oh, Jong-Tae Kim, Won-Jin Lee, Yoon Ha, Young-Il Yang and Keung-Nyun Kim

Int. J. Mol. Sci. 2021, 22(8), 4141; https://doi.org/10.3390/ijms22084141 - 16 Apr 2021

Cited by 16 | Viewed by 3312

Abstract

Stem cell therapy is one of the most promising candidate treatments for spinal cord injury. Research has shown optimistic results for this therapy, but clinical limitations remain, including poor viability, engraftment, and differentiation. Here, we isolated novel peripheral nerve-derived stem cells (PNSCs) from [...] Read more.

Stem cell therapy is one of the most promising candidate treatments for spinal cord injury. Research has shown optimistic results for this therapy, but clinical limitations remain, including poor viability, engraftment, and differentiation. Here, we isolated novel peripheral nerve-derived stem cells (PNSCs) from adult peripheral nerves with similar characteristics to neural-crest stem cells. These PNSCs expressed neural-crest specific markers and showed multilineage differentiation potential into Schwann cells, neuroglia, neurons, and mesodermal cells. In addition, PNSCs showed therapeutic potential by releasing the neurotrophic factors, including glial cell-line-derived neurotrophic factor, insulin-like growth factor, nerve growth factor, and neurotrophin-3. PNSC abilities were also enhanced by their development into spheroids which secreted neurotrophic factors several times more than non-spheroid PNSCs and expressed several types of extra cellular matrix. These features suggest that the potential for these PNSC spheroids can overcome their limitations. In an animal spinal cord injury (SCI) model, these PNSC spheroids induced functional recovery and neuronal regeneration. These PNSC spheroids also reduced the neuropathic pain which accompanies SCI after remyelination. These PNSC spheroids may represent a new therapeutic approach for patients suffering from SCI. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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17 pages, 6359 KiB

Open AccessArticle

Inhibition of Autophagy at Different Stages by ATG5 Knockdown and Chloroquine Supplementation Enhances Consistent Human Disc Cellular Apoptosis and Senescence Induction rather than Extracellular Matrix Catabolism

by Masaaki Ito, Takashi Yurube, Yutaro Kanda, Yuji Kakiuchi, Yoshiki Takeoka, Toru Takada, Ryosuke Kuroda and Kenichiro Kakutani

Int. J. Mol. Sci. 2021, 22(8), 3965; https://doi.org/10.3390/ijms22083965 - 12 Apr 2021

Cited by 21 | Viewed by 3151

Abstract

The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate [...] Read more.

The intervertebral disc is the largest avascular organ. Autophagy is an important cell survival mechanism by self-digestion and recycling damaged components under stress, primarily nutrient deprivation. Resident cells would utilize autophagy to cope with the harsh disc environment. Our objective was to elucidate the roles of human disc cellular autophagy. In human disc cells, serum deprivation and pro-inflammatory interleukin-1β (IL-1β) stimulation increased autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and decreased autophagy substrate p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. Then, RNA interference (RNAi) of autophagy-related gene 5 (ATG5), essential for autophagy, showed decreases in ATG5 protein (26.8%–27.4%, p < 0.0001), which suppressed early-stage autophagy with decreased LC3-II and increased p62/SQSTM1. Cell viability was maintained by ATG5 RNAi in serum-supplemented media (95.5%, p = 0.28) but reduced in serum-free media (80.4%, p = 0.0013) with IL-1β (69.9%, p = 0.0008). Moreover, ATG5 RNAi accelerated IL-1β-induced changes in apoptosis and senescence. Meanwhile, ATG5 RNAi unaffected IL-1β-induced catabolic matrix metalloproteinase release, down-regulated anabolic gene expression, and mitogen-activated protein kinase pathway activation. Lysosomotropic chloroquine supplementation presented late-stage autophagy inhibition with apoptosis and senescence induction, while catabolic enzyme production was modest. Disc-tissue analysis detected age-related changes in ATG5, LC3-II, and p62/SQSTM1. In summary, autophagy protects against human disc cellular apoptosis and senescence rather than extracellular matrix catabolism. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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18 pages, 3195 KiB

Open AccessArticle

Optimal Preclinical Conditions for Using Adult Human Multipotent Neural Cells in the Treatment of Spinal Cord Injury

by Jeong-Seob Won, Je Young Yeon, Hee-Jang Pyeon, Yu-Jeong Noh, Ji-Yoon Hwang, Chung Kwon Kim, Hyun Nam, Kyung-Hoon Lee, Sun-Ho Lee and Kyeung Min Joo

Int. J. Mol. Sci. 2021, 22(5), 2579; https://doi.org/10.3390/ijms22052579 - 4 Mar 2021

Cited by 10 | Viewed by 2775

Abstract

Stem cell-based therapeutics are amongst the most promising next-generation therapeutic approaches for the treatment of spinal cord injury (SCI), as they may promote the repair or regeneration of damaged spinal cord tissues. However, preclinical optimization should be performed before clinical application to guarantee [...] Read more.

Stem cell-based therapeutics are amongst the most promising next-generation therapeutic approaches for the treatment of spinal cord injury (SCI), as they may promote the repair or regeneration of damaged spinal cord tissues. However, preclinical optimization should be performed before clinical application to guarantee safety and therapeutic effect. Here, we investigated the optimal injection route and dose for adult human multipotent neural cells (ahMNCs) from patients with hemorrhagic stroke using an SCI animal model. ahMNCs demonstrate several characteristics associated with neural stem cells (NSCs), including the expression of NSC-specific markers, self-renewal, and multi neural cell lineage differentiation potential. When ahMNCs were transplanted into the lateral ventricle of the SCI animal model, they specifically migrated within 24 h of injection to the damaged spinal cord, where they survived for at least 5 weeks after injection. Although ahMNC transplantation promoted significant locomotor recovery, the injection dose was shown to influence treatment outcomes, with a 1 × 10⁶ (medium) dose of ahMNCs producing significantly better functional recovery than a 3 × 10⁵ (low) dose. There was no significant gain in effect with the 3 × 10⁶ ahMNCs dose. Histological analysis suggested that ahMNCs exert their effects by modulating glial scar formation, neuroprotection, and/or angiogenesis. These data indicate that ahMNCs from patients with hemorrhagic stroke could be used to develop stem cell therapies for SCI and that the indirect injection route could be clinically relevant. Moreover, the optimal transplantation dose of ahMNCs defined in this preclinical study might be helpful in calculating its optimal injection dose for patients with SCI in the future. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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20 pages, 3102 KiB

Open AccessArticle

Time-Course Changes of Extracellular Matrix Encoding Genes Expression Level in the Spinal Cord Following Contusion Injury—A Data-Driven Approach

by Andrea Bighinati, Zahra Khalajzeyqami, Vito Antonio Baldassarro, Luca Lorenzini, Maura Cescatti, Marzia Moretti, Luciana Giardino and Laura Calzà

Int. J. Mol. Sci. 2021, 22(4), 1744; https://doi.org/10.3390/ijms22041744 - 9 Feb 2021

Cited by 8 | Viewed by 2640

Abstract

The involvement of the extracellular matrix (ECM) in lesion evolution and functional outcome is well recognized in spinal cord injury. Most attention has been dedicated to the “core” area of the lesion and scar formation, while only scattered reports consider ECM modification based [...] Read more.

The involvement of the extracellular matrix (ECM) in lesion evolution and functional outcome is well recognized in spinal cord injury. Most attention has been dedicated to the “core” area of the lesion and scar formation, while only scattered reports consider ECM modification based on the temporal evolution and the segments adjacent to the lesion. In this study, we investigated the expression profile of 100 genes encoding for ECM proteins at 1, 8 and 45 days post-injury, in the spinal cord segments rostral and caudal to the lesion and in the scar segment, in a rat model. During both the active lesion phases and the lesion stabilization, we observed an asymmetric gene expression induced by the injury, with a higher regulation in the rostral segment of genes involved in ECM remodeling, adhesion and cell migration. Using bioinformatic approaches, the metalloproteases inhibitor Timp1 and the hyaluronan receptor Cd44 emerged as the hub genes at all post-lesion times. Results from the bioinformatic gene expression analysis were then confirmed at protein level by tissue analysis and by cell culture using primary astrocytes. These results indicated that ECM regulation also takes place outside of the lesion area in spinal cord injury. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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Review

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13 pages, 1138 KiB

Open AccessReview

Regeneration in Spinal Disease: Therapeutic Role of Hypoxia-Inducible Factor-1 Alpha in Regeneration of Degenerative Intervertebral Disc

by Jin-Woo Kim, Neunghan Jeon, Dong-Eun Shin, So-Young Lee, Myongwhan Kim, Dong Hun Han, Jae Yeon Shin and Soonchul Lee

Int. J. Mol. Sci. 2021, 22(10), 5281; https://doi.org/10.3390/ijms22105281 - 17 May 2021

Cited by 19 | Viewed by 4077

Abstract

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. [...] Read more.

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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19 pages, 1707 KiB

Open AccessReview

Stem Cell Therapy for Modulating Neuroinflammation in Neuropathic Pain

by Hari Prasad Joshi, Hyun-Jung Jo, Yong-Ho Kim, Seong-Bae An, Chul-Kyu Park and Inbo Han

Int. J. Mol. Sci. 2021, 22(9), 4853; https://doi.org/10.3390/ijms22094853 - 3 May 2021

Cited by 29 | Viewed by 6382

Abstract

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying [...] Read more.

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying disease mechanisms. Current pharmacological and nonpharmacological approaches can provide long-lasting pain relief to a limited percentage of patients and lack safe and effective treatment options. Therefore, scientists are focusing on the introduction of novel treatment approaches, such as stem cell therapy. A growing number of reports have highlighted the potential of stem cells for treating NP. In this review, we briefly introduce NP, current pharmacological and nonpharmacological treatments, and preclinical studies of stem cells to treat NP. In addition, we summarize stem cell mechanisms—including neuromodulation in treating NP. Literature searches were conducted using PubMed to provide an overview of the neuroprotective effects of stem cells with particular emphasis on recent translational research regarding stem cell-based treatment of NP, highlighting its potential as a novel therapeutic approach. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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14 pages, 2078 KiB

Open AccessReview

Molecular Targeted Therapy for the Bone Loss Secondary to Pyogenic Spondylodiscitis Using Medications for Osteoporosis: A Literature Review

by Takashi Ohnishi, Yuki Ogawa, Kota Suda, Miki Komatsu, Satoko Matsumoto Harmon, Mitsuru Asukai, Masahiko Takahata, Norimasa Iwasaki and Akio Minami

Int. J. Mol. Sci. 2021, 22(9), 4453; https://doi.org/10.3390/ijms22094453 - 24 Apr 2021

Cited by 5 | Viewed by 3462

Abstract

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, [...] Read more.

Pyogenic spondylodiscitis can cause severe osteolytic and destructive lesions in the spine. Elderly or immunocompromised individuals are particularly susceptible to infectious diseases; specifically, infections in the spine can impair the ability of the spine to support the trunk, causing patients to be bedridden, which can also severely affect the physical condition of patients. Although treatments for osteoporosis have been well studied, treatments for bone loss secondary to infection remain to be elucidated because they have pathological manifestations that are similar to but distinct from those of osteoporosis. Recently, we encountered a patient with severely osteolytic pyogenic spondylodiscitis who was treated with romosozumab and exhibited enhanced bone formation. Romosozumab stimulated canonical Wnt/β-catenin signaling, causing robust bone formation and the inhibition of bone resorption, which exceeded the bone loss secondary to infection. Bone loss due to infections involves the suppression of osteoblastogenesis by osteoblast apoptosis, which is induced by the nuclear factor-κB and mitogen-activated protein kinase pathways, and osteoclastogenesis with the receptor activator of the nuclear factor-κB ligand-receptor combination and subsequent activation of the nuclear factor of activated T cells cytoplasmic 1 and c-Fos. In this study, we review and discuss the molecular mechanisms of bone loss secondary to infection and analyze the efficacy of the medications for osteoporosis, focusing on romosozumab, teriparatide, denosumab, and bisphosphonates, in treating this pathological condition. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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24 pages, 1839 KiB

Open AccessReview

Understanding the Future Prospects of Synergizing Minimally Invasive Transforaminal Lumbar Interbody Fusion Surgery with Ceramics and Regenerative Cellular Therapies

by Wen-Cheng Lo, Lung-Wen Tsai, Yi-Shan Yang and Ryan Wing Yuk Chan

Int. J. Mol. Sci. 2021, 22(7), 3638; https://doi.org/10.3390/ijms22073638 - 31 Mar 2021

Cited by 9 | Viewed by 4170

Abstract

Transforaminal lumber interbody fusion (TLIF) is the last resort to address the lumber degenerative disorders such as spondylolisthesis, causing lower back pain. The current surgical intervention for these abnormalities includes open TLIF. However, in recent years, minimally invasive TLIF (MIS-TLIF) has gained a [...] Read more.

Transforaminal lumber interbody fusion (TLIF) is the last resort to address the lumber degenerative disorders such as spondylolisthesis, causing lower back pain. The current surgical intervention for these abnormalities includes open TLIF. However, in recent years, minimally invasive TLIF (MIS-TLIF) has gained a high momentum, as it could minimize the risk of infection, blood loss, and post-operative complications pertaining to fusion surgery. Further advancement in visualizing and guiding techniques along with grafting cage and materials are continuously improving the safety and efficacy of MIS-TLIF. These assistive techniques are also playing a crucial role to increase and improve the learning curve of surgeons. However, achieving an appropriate output through TLIF still remains a challenge, which might be synergized through 3D-printing and tissue engineering-based regenerative therapy. Owing to their differentiation potential, biomaterials such as stem/progenitor cells may contribute to restructuring lost or damaged tissues during MIS-TLIF, and this therapeutic efficacy could be further supplemented by platelet-derived biomaterials, leading to improved clinical outcomes. Thus, based on the above-mentioned strategies, we have comprehensively summarized recent developments in MIS-TLIF and its possible combinatorial regenerative therapies for rapid and long-term relief. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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18 pages, 2136 KiB

Open AccessReview

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

by Andreas S. Croft, Svenja Illien-Jünger, Sibylle Grad, Julien Guerrero, Sebastian Wangler and Benjamin Gantenbein

Int. J. Mol. Sci. 2021, 22(7), 3519; https://doi.org/10.3390/ijms22073519 - 29 Mar 2021

Cited by 38 | Viewed by 4155

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases)

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