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The Mechanistic Link between Cell Therapy and Neurorehabilitation
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The Mechanistic Link between Cell Therapy and Neurorehabilitation

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 (30 September 2020) | Viewed by 28142

Special Issue Editor

Dr. Naoki Tajiri

E-Mail Website
Guest Editor
Department of Neurophysiology & Brain Science, Graduate School of Medical Sciences & Medical School, Nagoya City University 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya-city, Aichi 467-8601, Japan
Interests: stem cell transplantation; neurological disorder; regenerative medicine; electric stimulation; rehabilitation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell therapy for neurological disorders has various meanings and offers a variety of potentials. Stem cells exist even in adulthood and possess the capacity to self-renew and differentiate into multiple lineages, contribute to normal homeostasis, and exert therapeutic benefits either endogenously or following transplantation in injured organs, i.e., the brain. The transplantation of exogenous cells, which include various stem/progenitor cells and differentiated cells, such as neurons with a specific phenotype, astrocytes, and oligodendrocytes, is readily referred to as a form of cell therapy. Transplanted cells might function as part of a newly developed network in the host tissue or secrete several trophic factors with subsequent neuroprotective/neurorestorative potentials.

Furthermore, exercise ameliorates the physical and cognitive impairment of patients with neurological disorders by enhancing brain plasticity, including increased neurogenesis and angiogenesis, as a major mechanism of action. Key to neuroplasticity is brain remodeling towards recapitulation of a neurodevelopmental microenvironment conducive to stem cell proliferation and differentiation.

However, a fundamental gap in our knowledge about the mechanistic link between stem cell and rehabilitation therapies remains unresolved. The novel concepts in this Special Issue embody the mechanistic link between cell therapy and neurorehabilitation, which I believe has direct research significance to various diseases, including neurological disorders.

Assoc. Prof. Naoki Tajiri
Guest Editor

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.

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Keywords

  • stem cells
  • transplantation
  • exercise
  • electric stimulation
  • neural circuit
  • neuroprotection
  • neurogenesis
  • angiogenesis
  • neurotrophic factors
  • cytokines

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Published Papers (7 papers)

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Research

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14 pages, 2155 KiB  
Article
Purinergic Receptor Blockade with Suramin Increases Survival of Postnatal Neural Progenitor Cells In Vitro
by Alejandro Herrera, Sara Morcuende, Rocío Talaverón, Beatriz Benítez-Temiño, Angel M. Pastor and Esperanza R. Matarredona
Int. J. Mol. Sci. 2021, 22(2), 713; https://doi.org/10.3390/ijms22020713 - 12 Jan 2021
Cited by 4 | Viewed by 2833
Abstract
Neural progenitor cells (NPCs) are self-renewing and multipotent cells that persist in the postnatal and adult brain in the subventricular zone and the hippocampus. NPCs can be expanded in vitro to be used in cell therapy. However, expansion is limited, since the survival [...] Read more.
Neural progenitor cells (NPCs) are self-renewing and multipotent cells that persist in the postnatal and adult brain in the subventricular zone and the hippocampus. NPCs can be expanded in vitro to be used in cell therapy. However, expansion is limited, since the survival and proliferation of adult NPCs decrease with serial passages. Many signaling pathways control NPC survival and renewal. Among these, purinergic receptor activation exerts differential effects on the biology of adult NPCs depending on the cellular context. In this study, we sought to analyze the effect of a general blockade of purinergic receptors with suramin on the proliferation and survival of NPCs isolated from the subventricular zone of postnatal rats, which are cultured as neurospheres. Treatment of neurospheres with suramin induced a significant increase in neurosphere diameter and in NPC number attributed to a decrease in apoptosis. Proliferation and multipotency were not affected. Suramin also induced an increase in the gap junction protein connexin43 and in vascular endothelial growth factor, which might be involved in the anti-apoptotic effect. Our results offer a valuable tool for increasing NPC survival before implantation in the lesioned brain and open the possibility of using this drug as adjunctive therapy to NPC transplantation. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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14 pages, 2426 KiB  
Article
Hydrogen Peroxide-Preconditioned Human Adipose-Derived Stem Cells Enhance the Recovery of Oligodendrocyte-Like Cells after Oxidative Stress-Induced Damage
by Patricia Garrido-Pascual, Ana Alonso-Varona, Begoña Castro, María Burón and Teodoro Palomares
Int. J. Mol. Sci. 2020, 21(24), 9513; https://doi.org/10.3390/ijms21249513 - 14 Dec 2020
Cited by 8 | Viewed by 2342
Abstract
Oxidative stress associated with neuroinflammation is a key process involved in the pathophysiology of neurodegenerative diseases, and therefore, has been proposed as a crucial target for new therapies. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a [...] Read more.
Oxidative stress associated with neuroinflammation is a key process involved in the pathophysiology of neurodegenerative diseases, and therefore, has been proposed as a crucial target for new therapies. Recently, the therapeutic potential of human adipose-derived stem cells (hASCs) has been investigated as a novel strategy for neuroprotection. These cells can be preconditioned by exposing them to mild stress in order to improve their response to oxidative stress. In this study, we evaluate the therapeutic potential of hASCs preconditioned with low doses of H2O2 (called HC016 cells) to overcome the deleterious effect of oxidative stress in an in vitro model of oligodendrocyte-like cells (HOGd), through two strategies: i, the culture of oxidized HOGd with HC016 cell-conditioned medium (CM), and ii, the indirect co-culture of oxidized HOGd with HC016 cells, which had or had not been exposed to oxidative stress. The results demonstrated that both strategies had reparative effects, oxidized HC016 cell co-culture being the one associated with the greatest recovery of the damaged HOGd, increasing their viability, reducing their intracellular reactive oxygen species levels and promoting their antioxidant capacity. Taken together, these findings support the view that HC016 cells, given their reparative capacity, might be considered an important breakthrough in cell-based therapies. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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9 pages, 1869 KiB  
Article
Generation of Cochlear Hair Cells from Sox2 Positive Supporting Cells via DNA Demethylation
by Xin Deng and Zhengqing Hu
Int. J. Mol. Sci. 2020, 21(22), 8649; https://doi.org/10.3390/ijms21228649 - 17 Nov 2020
Cited by 8 | Viewed by 2652
Abstract
Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into [...] Read more.
Regeneration of auditory hair cells in adult mammals is challenging. It is also difficult to track the sources of regenerated hair cells, especially in vivo. Previous paper found newly generated hair cells in deafened mouse by injecting a DNA methyltransferase inhibitor 5-azacytidine into the inner ear. This paper aims to investigate the cell sources of new hair cells. Transgenic mice with enhanced green fluorescent protein (EGFP) expression controlled by the Sox2 gene were used in the study. A combination of kanamycin and furosemide was applied to deafen adult mice, which received 4 mM 5-azacytidine injection into the inner ear three days later. Mice were followed for 3, 5, 7 and 14 days after surgery to track hair cell regeneration. Immunostaining of Myosin VIIa and EGFP signals were used to track the fate of Sox2-expressing supporting cells. The results show that (i) expression of EGFP in the transgenic mice colocalized the supporting cells in the organ of Corti, and (ii) the cell source of regenerated hair cells following 5-azacytidine treatment may be supporting cells during 5–7 days post 5-azacytidine injection. In conclusion, 5-azacytidine may promote the conversion of supporting cells to hair cells in chemically deafened adult mice. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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17 pages, 4955 KiB  
Article
Capacity of Retinal Ganglion Cells Derived from Human Induced Pluripotent Stem Cells to Suppress T-Cells
by Ayaka Edo, Sunao Sugita, Yoko Futatsugi, Junki Sho, Akishi Onishi, Yoshiaki Kiuchi and Masayo Takahashi
Int. J. Mol. Sci. 2020, 21(21), 7831; https://doi.org/10.3390/ijms21217831 - 22 Oct 2020
Cited by 9 | Viewed by 3415
Abstract
Retinal ganglion cells (RGCs) are impaired in patients such as those with glaucoma and optic neuritis, resulting in permanent vision loss. To restore visual function, development of RGC transplantation therapy is now underway. Induced pluripotent stem cells (iPSCs) are an important source of [...] Read more.
Retinal ganglion cells (RGCs) are impaired in patients such as those with glaucoma and optic neuritis, resulting in permanent vision loss. To restore visual function, development of RGC transplantation therapy is now underway. Induced pluripotent stem cells (iPSCs) are an important source of RGCs for human allogeneic transplantation. We therefore analyzed the immunological characteristics of iPSC-derived RGCs (iPSC-RGCs) to evaluate the possibility of rejection after RGC transplantation. We first assessed the expression of human leukocyte antigen (HLA) molecules on iPSC-RGCs using immunostaining, and then evaluated the effects of iPSC-RGCs to activate lymphocytes using the mixed lymphocyte reaction (MLR) and iPSC-RGC co-cultures. We observed low expression of HLA class I and no expression of HLA class II molecules on iPSC-RGCs. We also found that iPSC-RGCs strongly suppressed various inflammatory immune cells including activated T-cells in the MLR assay and that transforming growth factor-β2 produced by iPSC-RGCs played a critical role in suppression of inflammatory cells in vitro. Our data suggest that iPSC-RGCs have low immunogenicity, and immunosuppressive capacity on lymphocytes. Our study will contribute to predicting immune attacks after RGC transplantation. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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20 pages, 1563 KiB  
Article
Indonesian Ginger (Bangle) Extract Promotes Neurogenesis of Human Neural Stem Cells through WNT Pathway Activation
by Kazumi Hirano, Miwa Kubo, Yoshiyasu Fukuyama and Masakazu Namihira
Int. J. Mol. Sci. 2020, 21(13), 4772; https://doi.org/10.3390/ijms21134772 - 5 Jul 2020
Cited by 6 | Viewed by 5037
Abstract
Indonesian ginger (Zingiber purpureum Rosc.), also known as Bangle, exhibits neurotrophic effects on cultured murine cortical neurons and in the adult mouse brain, but the underlying mechanisms remain unknown. Here, using human fetal neural stem cells (hfNSCs) as a model system for [...] Read more.
Indonesian ginger (Zingiber purpureum Rosc.), also known as Bangle, exhibits neurotrophic effects on cultured murine cortical neurons and in the adult mouse brain, but the underlying mechanisms remain unknown. Here, using human fetal neural stem cells (hfNSCs) as a model system for in vitro human neurogenesis, we show that Bangle extracts activate canonical WNT/β-catenin signaling. Bangle extract-treatment of hfNSCs not only promoted neuronal differentiation, but also accelerated neurite outgrowth from immature neurons. Furthermore, Bangle extracts induced expression of neurogenic genes and WNT signaling-target genes, and facilitated the accumulation of β-catenin in nuclei of hfNSC. Interestingly, altered histone modifications were also observed in Bangle-treated hfNSCs. Together, these findings demonstrate that Bangle contributes to hfNSC neurogenesis by WNT pathway and epigenetic regulation. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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Review

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12 pages, 254 KiB  
Review
Recent Advances in Stem Cell Therapies to Address Neuroinflammation, Stem Cell Survival, and the Need for Rehabilitative Therapies to Treat Traumatic Brain Injuries
by George R. Bjorklund, Trent R. Anderson and Sarah E. Stabenfeldt
Int. J. Mol. Sci. 2021, 22(4), 1978; https://doi.org/10.3390/ijms22041978 - 17 Feb 2021
Cited by 13 | Viewed by 3206
Abstract
Traumatic brain injuries (TBIs) are a significant health problem both in the United States and worldwide with over 27 million cases being reported globally every year. TBIs can vary significantly from a mild TBI with short-term symptoms to a moderate or severe TBI [...] Read more.
Traumatic brain injuries (TBIs) are a significant health problem both in the United States and worldwide with over 27 million cases being reported globally every year. TBIs can vary significantly from a mild TBI with short-term symptoms to a moderate or severe TBI that can result in long-term or life-long detrimental effects. In the case of a moderate to severe TBI, the primary injury causes immediate damage to structural tissue and cellular components. This may be followed by secondary injuries that can be the cause of chronic and debilitating neurodegenerative effects. At present, there are no standard treatments that effectively target the primary or secondary TBI injuries themselves. Current treatment strategies often focus on addressing post-injury symptoms, including the trauma itself as well as the development of cognitive, behavioral, and psychiatric impairment. Additional therapies such as pharmacological, stem cell, and rehabilitative have in some cases shown little to no improvement on their own, but when applied in combination have given encouraging results. In this review, we will abridge and discuss some of the most recent research advances in stem cell therapies, advanced engineered biomaterials used to support stem transplantation, and the role of rehabilitative therapies in TBI treatment. These research examples are intended to form a multi-tiered perspective for stem-cell therapies used to treat TBIs; stem cells and stem cell products to mitigate neuroinflammation and provide neuroprotective effects, biomaterials to support the survival, migration, and integration of transplanted stem cells, and finally rehabilitative therapies to support stem cell integration and compensatory and restorative plasticity. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
21 pages, 38792 KiB  
Review
Regenerative Rehabilitation for Stroke Recovery by Inducing Synergistic Effects of Cell Therapy and Neurorehabilitation on Motor Function: A Narrative Review of Pre-Clinical Studies
by Akira Ito, Naoko Kubo, Nan Liang, Tomoki Aoyama and Hiroshi Kuroki
Int. J. Mol. Sci. 2020, 21(9), 3135; https://doi.org/10.3390/ijms21093135 - 29 Apr 2020
Cited by 10 | Viewed by 8015
Abstract
Neurological diseases severely affect the quality of life of patients. Although existing treatments including rehabilitative therapy aim to facilitate the recovery of motor function, achieving complete recovery remains a challenge. In recent years, regenerative therapy has been considered as a potential candidate that [...] Read more.
Neurological diseases severely affect the quality of life of patients. Although existing treatments including rehabilitative therapy aim to facilitate the recovery of motor function, achieving complete recovery remains a challenge. In recent years, regenerative therapy has been considered as a potential candidate that could yield complete functional recovery. However, to achieve desirable results, integration of transplanted cells into neural networks and generation of appropriate microenvironments are essential. Furthermore, considering the nascent state of research in this area, we must understand certain aspects about regenerative therapy, including specific effects, nature of interaction when administered in combination with rehabilitative therapy (regenerative rehabilitation), and optimal conditions. Herein, we review the current status of research in the field of regenerative therapy, discuss the findings that could hold the key to resolving the challenges associated with regenerative rehabilitation, and outline the challenges to be addressed with future studies. The current state of research emphasizes the importance of determining the independent effect of regenerative and rehabilitative therapies before exploring their combined effects. Furthermore, the current review highlights the progression in the treatment perspective from a state of compensation of lost function to that of a possibility of complete functional recovery. Full article
(This article belongs to the Special Issue The Mechanistic Link between Cell Therapy and Neurorehabilitation)
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