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Biology
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Models of CNS Regeneration: Mind the Gap!
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Models of CNS Regeneration: Mind the Gap!

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 21214

Special Issue Editor

Prof. Dr. Eustace Johnson

E-Mail Website
Guest Editor
Faculty of Medicine, Dentistry and Life Sciences, University of Chester, Parkgate Road, Chester CH1 4BJ, UK
Interests: stem cells; regenerative medicine; tissue engineering; musculoskeletal; spine

Special Issue Information

Dear Colleagues,

The regeneration of the central nervous system (CNS) remains an elusive target for basic researchers and clinicians in regenerative medicine. Progress in rodent models using stem cells to decrease the catastrophic effects of CNS damage and increase axonal growth has failed to translate to successful clinical treatment of humans. Clearly, there is a knowledge gap. This Special Issue aims to help bridge this gap by addressing how alternative approaches have been used to better understand mechanisms of CNS regeneration. Contributions from researchers across the field will present the latest research findings and discuss how this research helps provide a bigger picture of CNS regeneration across species and across evolutionary pressures, including in vivo, ex vivo, and in vitro models, encompassing adult stem cells, pluripotent stem cells, plasticity, systemic issues, and the wound microenvironment. In this way, the Special Issue will provide both an overview of our current knowledge from these alternative models and bring together expert opinion on what still needs to be discovered and translated to help improve the likelihood of successfully regenerating the human CNS.

Prof. Eustace Johnson
Guest Editor

Manuscript Submission Information

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Keywords

  • stem cell biology
  • central nervous system
  • axonal regeneration
  • model organism
  • in vivo
  • in vitro
  • clinical translation

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Published Papers (5 papers)

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Research

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12 pages, 3070 KiB  
Article
Application of Autologous Peripheral Blood Mononuclear Cells into the Area of Spinal Cord Injury in a Subacute Period: A Feasibility Study in Pigs
by Iliya Shulman, Sergei Ogurcov, Alexander Kostennikov, Alexander Rogozin, Ekaterina Garanina, Galina Masgutova, Mikhail Sergeev, Albert Rizvanov and Yana Mukhamedshina
Biology 2021, 10(2), 87; https://doi.org/10.3390/biology10020087 - 24 Jan 2021
Cited by 6 | Viewed by 2710
Abstract
Peripheral blood presents an available source of cells for both fundamental research and clinical use. In our study, we have evaluated the therapeutic potential of peripheral blood mononuclear cells (PBMCs) excluding the preliminary sorting or mobilization of peripheral blood stem cells. We have [...] Read more.
Peripheral blood presents an available source of cells for both fundamental research and clinical use. In our study, we have evaluated the therapeutic potential of peripheral blood mononuclear cells (PBMCs) excluding the preliminary sorting or mobilization of peripheral blood stem cells. We have evaluated the regenerative potential of PBMCs embedded into a fibrin matrix (FM) in a model of pig spinal cord injury. The distribution of transplanted PBMCs in the injured spinal cord was evaluated; PBMCs were shown to penetrate into the deep layers of the spinal cord and concentrate mainly in the grey matter. The results of the current study revealed an increase in the tissue integrity in the area adjacent to the epicenter of injury and the partially restored conduction along posterior columns of the spinal cord in animals after FM+PBMC application. The multiplex analysis of blood serum and cerebrospinal fluid showed the cytokine imbalance to occur without significantly shifting toward pro-inflammatory or anti-inflammatory cytokine cascades. Full article
(This article belongs to the Special Issue Models of CNS Regeneration: Mind the Gap!)
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24 pages, 6042 KiB  
Article
Ex Vivo Rat Transected Spinal Cord Slices as a Model to Assess Lentiviral Vector Delivery of Neurotrophin-3 and Short Hairpin RNA against NG2
by Azim Patar, Peter Dockery, Siobhan McMahon and Linda Howard
Biology 2020, 9(3), 54; https://doi.org/10.3390/biology9030054 - 15 Mar 2020
Cited by 3 | Viewed by 4544
Abstract
The failure of the spinal cord to regenerate can be attributed both to a lack of trophic support for regenerating axons and to upregulation of inhibitory factors such as chondroitin sulphate proteoglycans including NG2 following injury. Lentiviral vector-mediated gene therapy is a possible [...] Read more.
The failure of the spinal cord to regenerate can be attributed both to a lack of trophic support for regenerating axons and to upregulation of inhibitory factors such as chondroitin sulphate proteoglycans including NG2 following injury. Lentiviral vector-mediated gene therapy is a possible strategy for treating spinal cord injury (SCI). This study investigated the effect of lentiviral vectors expressing Neurotrophin-3 (NT-3) and short-hairpin RNA against NG2 (NG2 sh) to enhance neurite outgrowth in in vitro and ex vivo transection injury models. Conditioned medium from cells transduced with NT-3 or shNG2 lentiviruses caused a significant increase in neurite length of primary dorsal root ganglia neurons compared to the control group in vitro. In an ex vivo organotypic slice culture (OSC) transduction with Lenti-NT-3 promoted axonal growth. Transducing OSCs with a combination of Lenti-NT-3/NG2 sh lead to a further increase in axonal growth but only in injured slices and only within the region adjacent to the site of injury. These findings suggest that the combination of lentiviral NT-3 and NG2 sh reduced NG2 levels and provided a more favourable microenvironment for neuronal regeneration after SCI. This study also shows that OSCs may be a useful platform for studying glial scarring and potential SCI treatments. Full article
(This article belongs to the Special Issue Models of CNS Regeneration: Mind the Gap!)
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16 pages, 2209 KiB  
Article
Contributions of Chondroitin Sulfate, Keratan Sulfate and N-linked Oligosaccharides to Inhibition of Neurite Outgrowth by Aggrecan
by Thomas M. Hering, Justin A. Beller, Christopher M. Calulot and Diane M. Snow
Biology 2020, 9(2), 29; https://doi.org/10.3390/biology9020029 - 12 Feb 2020
Cited by 9 | Viewed by 4135
Abstract
The role of proteoglycans in the central nervous system (CNS) is a rapidly evolving field and has major implications in the field of CNS injury. Chondroitin sulfate proteoglycans (CSPGs) increase in abundance following damage to the spinal cord and inhibit neurite outgrowth. Major [...] Read more.
The role of proteoglycans in the central nervous system (CNS) is a rapidly evolving field and has major implications in the field of CNS injury. Chondroitin sulfate proteoglycans (CSPGs) increase in abundance following damage to the spinal cord and inhibit neurite outgrowth. Major advances in understanding the interaction between outgrowing neurites and CSPGs has created a need for more robust and quantitative analyses to further our understanding of this interaction. We report the use of a high-throughput assay to determine the effect of various post-translational modifications of aggrecan upon neurite outgrowth from NS-1 cells (a PC12 cell line derivative). Aggrecan contains chondroitin sulfate, keratan sulfate, and N-linked oligosaccharides (N-glycans), each susceptible to removal through different enzymatic digestions. Using a sequential digestion approach, we found that chondroitin sulfate and N-glycans, but not keratan sulfate, contribute to inhibition of neurite outgrowth by substrate-bound aggrecan. For the first time, we have shown that N-linked oligosaccharides on aggrecan contribute to its inhibition of neuritogenesis. Full article
(This article belongs to the Special Issue Models of CNS Regeneration: Mind the Gap!)
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15 pages, 4979 KiB  
Article
The Use of Myelinating Cultures as a Screen of Glycomolecules for CNS Repair
by George A. McCanney, Susan L. Lindsay, Michael A. McGrath, Hugh J. Willison, Claire Moss, Charles Bavington and Susan C. Barnett
Biology 2019, 8(3), 52; https://doi.org/10.3390/biology8030052 - 28 Jun 2019
Cited by 4 | Viewed by 4709
Abstract
In vitro cell-based assays have been fundamental in modern drug discovery and have led to the identification of novel therapeutics. We have developed complex mixed central nervous system (CNS) cultures, which recapitulate the normal process of myelination over time and allow the study [...] Read more.
In vitro cell-based assays have been fundamental in modern drug discovery and have led to the identification of novel therapeutics. We have developed complex mixed central nervous system (CNS) cultures, which recapitulate the normal process of myelination over time and allow the study of several parameters associated with CNS damage, both during development and after injury or disease. In particular, they have been used as a reliable screen to identify drug candidates that may promote (re)myelination and/or neurite outgrowth. Previously, using these cultures, we demonstrated that a panel of low sulphated heparin mimetics, with structures similar to heparan sulphates (HSs), can reduce astrogliosis, and promote myelination and neurite outgrowth. HSs reside in either the extracellular matrix or on the surface of cells and are thought to modulate cell signaling by both sequestering ligands, and acting as co-factors in the formation of ligand-receptor complexes. In this study, we have used these cultures as a screen to address the repair potential of numerous other commercially available sulphated glycomolecules, namely heparosans, ulvans, and fucoidans. These compounds are all known to have certain characteristics that mimic cellular glycosaminoglycans, similar to heparin mimetics. We show that the N-sulphated heparosans promoted myelination. However, O-sulphated heparosans did not affect myelination but promoted neurite outgrowth, indicating the importance of structure in HS function. Moreover, neither highly sulphated ulvans nor fucoidans had any effect on remyelination but CX-01, a low sulphated porcine intestinal heparin, promoted remyelination in vitro. These data illustrate the use of myelinating cultures as a screen and demonstrate the potential of heparin mimetics as CNS therapeutics. Full article
(This article belongs to the Special Issue Models of CNS Regeneration: Mind the Gap!)
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Review

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23 pages, 3247 KiB  
Review
The Comparative Effects of Mesenchymal Stem Cell Transplantation Therapy for Spinal Cord Injury in Humans and Animal Models: A Systematic Review and Meta-Analysis
by Louis D. V. Johnson, Mark R. Pickard and William E. B. Johnson
Biology 2021, 10(3), 230; https://doi.org/10.3390/biology10030230 - 16 Mar 2021
Cited by 25 | Viewed by 4291
Abstract
Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. [...] Read more.
Animal models have been used in preclinical research to examine potential new treatments for spinal cord injury (SCI), including mesenchymal stem cell (MSC) transplantation. MSC transplants have been studied in early human trials. Whether the animal models represent the human studies is unclear. This systematic review and meta-analysis has examined the effects of MSC transplants in human and animal studies. Following searches of PubMed, Clinical Trials and the Cochrane Library, published papers were screened, and data were extracted and analysed. MSC transplantation was associated with significantly improved motor and sensory function in humans, and significantly increased locomotor function in animals. However, there are discrepancies between the studies of human participants and animal models, including timing of MSC transplant post-injury and source of MSCs. Additionally, difficulty in the comparison of functional outcome measures across species limits the predictive nature of the animal research. These findings have been summarised, and recommendations for further research are discussed to better enable the translation of animal models to MSC-based human clinical therapy. Full article
(This article belongs to the Special Issue Models of CNS Regeneration: Mind the Gap!)
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