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Regeneration for Spinal Diseases 4.0

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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: 20 December 2024 | Viewed by 13109

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Special Issue Editors

Prof. Dr. Inbo Han

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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
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Dr. Takashi Yurube

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Guest Editor

Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
Interests: minimally invasive reconstruction; spine surgery; regenerative medicine
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Dr. Daisuke Sakai

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Guest Editor

Department Orthopaedic Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Japan
Interests: intervertebral disc regeneration; stem cells; scoliosis; regenerative medicine
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 Diseases”. 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, 2nd, and 3rd editions, we would like to add more results and new insights from recent research projects.

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

https://www.mdpi.com/journal/ijms/special_issues/Spinal_Diseases_2

https://www.mdpi.com/journal/ijms/special_issues/MZN0W0CUIU

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

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

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Keywords

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

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Published Papers (7 papers)

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Research

11 pages, 2333 KiB

Open AccessArticle

Optimal Intermittent Administration Interval of Abaloparatide for Bone Morphogenetic Protein-Induced Bone Formation in a Rat Spinal Fusion Model

by Tetsutaro Abe, Masashi Miyazaki, Noriaki Sako, Shozo Kanezaki, Yuta Tsubouchi and Nobuhiro Kaku

Int. J. Mol. Sci. 2024, 25(7), 3655; https://doi.org/10.3390/ijms25073655 - 25 Mar 2024

Viewed by 1044

Abstract

Both bone morphogenetic protein 2 (BMP-2) and abaloparatide are used to promote bone formation. However, there is no consensus about their optimal administration. We investigated the optimal administration theory for the pairing of BMP-2 and abaloparatide in a rat spinal fusion model. Group I was only implanted in carriers and saline. Carriers with 3 µg of recombinant human BMP-2 (rhBMP-2) were implanted in other groups. Abaloparatide injections were administered three times a week for group III (for a total amount of 120 µg/kg in a week) and six times a week for group IV (for a total amount of 120 µg/kg in a week) after surgery. They were euthanized 8 weeks after the surgery, and we explanted their spines at that time. We assessed them using manual palpation tests, radiography, high-resolution micro-computed tomography (micro-CT), and histological analysis. We also analyzed serum bone metabolism markers. The fusion rate in Groups III and IV was higher than in Group I, referring to the manual palpation tests. Groups III and IV recorded greater radiographic scores than those in Groups I and II, too. Micro-CT analysis showed that Tbs. Sp in Groups III and IV was significantly lower than in Group I. Tb. N in Group IV was significantly higher than in Group I. Serum marker analysis showed that bone formation markers were higher in Groups III and IV than in Group I. On the other hand, bone resorption markers were lower in Group IV than in Group I. A histological analysis showed enhanced trabecular bone osteogenesis in Group IV. Frequent administration of abaloparatide may be suitable for the thickening of trabecular bone structure and the enhancement of osteogenesis in a rat spinal fusion model using BMP-2 in insufficient doses. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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15 pages, 18861 KiB

Open AccessArticle

Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p

by Yutaka Morishima, Masahito Kawabori, Kazuyoshi Yamazaki, Soichiro Takamiya, Sho Yamaguchi, Yo Nakahara, Hajime Senjo, Daigo Hashimoto, Sakiko Masuda, Yoichiro Fujioka, Yusuke Ohba, Yuki Mizuno, Yuji Kuge and Miki Fujimura

Int. J. Mol. Sci. 2024, 25(4), 2406; https://doi.org/10.3390/ijms25042406 - 18 Feb 2024

Cited by 6 | Viewed by 2957

Abstract

Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood–brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using ⁶⁴Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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24 pages, 37272 KiB

Open AccessArticle

Improved Efficacy of Delayed Treatment with Human Bone Marrow-Derived Stromal Cells Evaluated in Rats with Spinal Cord Injury

by Marta Aguado-Garrido, Concepción García-Rama, Lorenzo Romero-Ramírez, Vinnitsa Buzoianu-Anguiano, Enrique Pérez-Rizo, Boris W. Kramer and Jörg Mey

Int. J. Mol. Sci. 2024, 25(3), 1548; https://doi.org/10.3390/ijms25031548 - 26 Jan 2024

Cited by 1 | Viewed by 1377

Abstract

The treatment of spinal cord injury (SCI) with uncultivated human bone marrow-derived stromal cells (bmSCs) prepared by negative selection has been proposed to be therapeutically superior to treatment with stem cells that were expanded in vitro. To explore their use in clinical trials, we studied the functional effects of delayed application at 7 days after SCI by testing different doses of bmSCs. Spinal cord contusion injury was induced in adult male Wistar rats at the thoracic level T9. Human bmSCs were prepared by negative selection without expansion in vitro (NeuroCells^TM). Treatment consisted of one 150 µL injection into the cisterna magna containing 0.5 or 2.5 million fresh bmSCs or 2.5 million bmSCs. The recovery of motor functions was evaluated during a surveillance period of six weeks (6 W), during which spinal cords were assessed histologically. Treatment resulted in a significant, dose-dependent therapeutic effect on the recovery of motor performance. The histological analysis revealed a lower degree of axonal degeneration and better survival of neurons and oligodendrocytes in bmSCs treated rats. Our results support delayed intrathecal application of bmSCs prepared by negative selection without expansion in vitro as a treatment of SCI. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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19 pages, 5124 KiB

Open AccessArticle

Safety and Feasibility of Intradiscal Administration of Matrilin-3-Primed Adipose-Derived Mesenchymal Stromal Cell Spheroids for Chronic Discogenic Low Back Pain: Phase 1 Clinical Trial

by Dong Hyun Lee, Kwang-Sook Park, Hae Eun Shin, Sung Bum Kim, Hyejeong Choi, Seong Bae An, Hyemin Choi, Joo Pyung Kim and Inbo Han

Int. J. Mol. Sci. 2023, 24(23), 16827; https://doi.org/10.3390/ijms242316827 - 27 Nov 2023

Cited by 5 | Viewed by 1477

Abstract

Functionally enhanced mesenchymal stromal cells participate in the repair of intervertebral disc. This study aimed to assess the safety and tolerability of intradiscal administration of matrilin-3-primed adipose-derived stromal cell (ASC) spheroids with hyaluronic acid (HA) in patients with chronic discogenic low back pain (LBP). In this single-arm, open-label phase I clinical trial, eight patients with chronic discogenic LBP were observed over 6 months. Each patient underwent a one-time intradiscal injection of 1 mL of 6.0 × 10⁶ cells/disc combined with HA under real-time fluoroscopic guidance. Safety and feasibility were gauged using Visual Analogue Scale (VAS) pain and Oswestry Disability Index (ODI) scores and magnetic resonance imaging. All participants remained in the trial, with no reported adverse events linked to the procedure or stem cells. A successful outcome-marked by a minimum 2-point improvement in the VAS pain score and a 10-point improvement in ODI score from the start were observed in six participants. Although the modified Pfirrmann grade remained consistent across all participants, radiological improvements were evident in four patients. Specifically, two patients exhibited reduced high-intensity zones while another two demonstrated decreased disc protrusion. In conclusion, the intradiscal application of matrilin-3-primed ASC spheroids with HA is a safe and feasible treatment option for chronic discogenic LBP. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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16 pages, 2003 KiB

Open AccessArticle

Recombinant Laminin-511 Fragment (iMatrix-511) Coating Supports Maintenance of Human Nucleus Pulposus Progenitor Cells In Vitro

by Hazuki Soma, Daisuke Sakai, Yoshihiko Nakamura, Shota Tamagawa, Takayuki Warita, Jordy Schol, Erika Matsushita, Mitsuru Naiki, Masato Sato and Masahiko Watanabe

Int. J. Mol. Sci. 2023, 24(23), 16713; https://doi.org/10.3390/ijms242316713 - 24 Nov 2023

Cited by 6 | Viewed by 1728

Abstract

The angiopoietin-1 receptor (Tie2) marks specific nucleus pulposus (NP) progenitor cells, shows a rapid decline during aging and intervertebral disc degeneration, and has thus sparked interest in its utilization as a regenerative agent against disc degeneration. However, the challenge of maintaining and expanding these progenitor cells in vitro has been a significant hurdle. In this study, we investigated the potential of laminin-511 to sustain Tie2⁺ NP progenitor cells in vitro. We isolated cells from human NP tissue (n = 5) and cultured them for 6 days on either standard (Non-coat) or iMatrix-511 (laminin-511 product)-coated (Lami-coat) dishes. We assessed these cells for their proliferative capacity, activation of Erk1/2 and Akt pathways, as well as the expression of cell surface markers such as Tie2, GD2, and CD24. To gauge their regenerative potential, we examined their extracellular matrix (ECM) production capacity (intracellular type II collagen (Col2) and proteoglycans (PG)) and their ability to form spherical colonies within methylcellulose hydrogels. Lami-coat significantly enhanced cell proliferation rates and increased Tie2 expression, resulting in a 7.9-fold increase in Tie2-expressing cell yields. Moreover, the overall proportion of cells positive for Tie2 also increased 2.7-fold. Notably, the Col2 positivity rate was significantly higher on laminin-coated plates (Non-coat: 10.24% (±1.7%) versus Lami-coat: 26.2% (±7.5%), p = 0.010), and the ability to form spherical colonies also showed a significant improvement (Non-coat: 40.7 (±8.8)/1000 cells versus Lami-coat: 70.53 (±18.0)/1000 cells, p = 0.016). These findings demonstrate that Lami-coat enhances the potential of NP cells, as indicated by improved colony formation and proliferative characteristics. This highlights the potential of laminin-coating in maintaining the NP progenitor cell phenotype in culture, thereby supporting their translation into prospective clinical cell-transplantation products. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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29 pages, 46035 KiB

Open AccessArticle

Enhanced Intervertebral Disc Repair via Genetically Engineered Mesenchymal Stem Cells with Tetracycline Regulatory System

by Yeji Kim, Seong Bae An, Sang-Hyuk Lee, Jong Joo Lee, Sung Bum Kim, Jae-Cheul Ahn, Dong-Youn Hwang and Inbo Han

Int. J. Mol. Sci. 2023, 24(22), 16024; https://doi.org/10.3390/ijms242216024 - 7 Nov 2023

Cited by 1 | Viewed by 2257

Abstract

The therapeutic potential of Mesenchymal stem cells (MSCs) for the treatment of Intervertebral disc (IVD) degeneration can be enhanced by amplifying specific cytokines and proteins. This study aimed to investigate the therapeutic potential of tetracycline-off system-engineered tonsil-derived mesenchymal stem cells (ToMSC-Tetoff-TGFβ1-IGF1-BMP7) for treating intervertebral disc (IVD) degeneration. ToMSCs were isolated from a tonsillectomy patient and genetically modified with four distinct plasmids via CRISPR/Cas9-mediated knock-in gene editing. Transgene expression was confirmed through immunofluorescence, western blots, and an enzyme-linked immunosorbent assay for transforming growth factor beta 1 (TGFβ1) protein secretion, and the effect of MSC-TetOff-TGFβ1-IGF1-BMP7 on disc injury was assessed in a rat model. The ToMSC-Tetoff-TGFβ1-IGF1-BMP7 treatment exhibited superior therapeutic effects compared to ToMSC-TGFβ1, and ToMSC-SDF1α implantation groups, stimulating the regeneration of nucleus pulposus (NP) cells crucial for IVD. The treatment showed potential to restore the structural integrity of the extracellular matrix (ECM) by upregulating key molecules such as aggrecan and type II collagen. It also exhibited anti-inflammatory properties and reduced pain-inducing neuropeptides. ToMSC-Tetoff-TGFβ1-IGF1-BMP7 holds promise as a novel treatment for IVD degeneration. It appears to promote NP cell regeneration, restore ECM structure, suppress inflammation, and reduce pain. However, more research and clinical trials are required to confirm its therapeutic potential. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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16 pages, 10720 KiB

Open AccessArticle

Expression of Glial-Cell-Line-Derived Neurotrophic Factor Family Ligands in Human Intervertebral Discs

by Tatsuya Iwasaki, Koji Akeda, Koki Kawaguchi, Junichi Yamada, Takahiro Hasegawa, Norihiko Takegami, Tatsuhiko Fujiwara and Akihiro Sudo

Int. J. Mol. Sci. 2023, 24(21), 15874; https://doi.org/10.3390/ijms242115874 - 1 Nov 2023

Viewed by 1494

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) family ligands (GFLs) contribute to the sensitization of primary afferents and are involved in the pathogenesis of inflammatory pain. The purpose of this preliminary study was to examine the expression of other GFLs (neurturin (NRTN), artemin (ARTN), persephin (PSPN)) and receptors in human IVD cells and tissues exhibiting early and advanced stages of degeneration. Human IVD cells were cultured as a monolayer after isolation from the nucleus pulposus (NP) and anulus fibrosus (AF) tissues. The mRNA expression of NRTN, ARTN, PSPN, and their receptors (GFRA2–GFRA4) was quantified using real-time PCR. Protein expression was evaluated using immunohistochemistry and Western blotting. The expression of NRTN, ARTN, PSPN, and their co-receptors (GFRA2-GFRA4) was identified in human IVD cells at both mRNA and protein levels. A trend was noted wherein the mRNA expression of ARTN, PSPN, and GFRA2 was upregulated by IL-1β treatment in a dose-dependent manner. The percentages of immunopositive cells in the advanced degenerate stage of ARTN, PSPN, and GFRA2 were significantly higher than those in the early degenerate stage. Their expression was enhanced in advanced tissue degeneration, which suggests that GFLs (ARTN and PSPN) may be involved in the pathogenesis of discogenic pain. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 4.0)

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