scholarly journals Bone Marrow-Derived Cells as a Therapeutic Approach to Optic Nerve Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Louise A. Mesentier-Louro ◽  
Camila Zaverucha-do-Valle ◽  
Paulo H. Rosado-de-Castro ◽  
Almir J. Silva-Junior ◽  
Pedro M. Pimentel-Coelho ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Optic Nerve ◽  
Mononuclear Cells ◽  
Ganglion Cells ◽  
Therapeutic Effects ◽  
Cell Therapies ◽  
Routes Of Administration ◽  
Optic Nerve Diseases ◽  
The Central Nervous System ◽  
Bone Marrow Derived Cells

Following optic nerve injury associated with acute or progressive diseases, retinal ganglion cells (RGCs) of adult mammals degenerate and undergo apoptosis. These diseases have limited therapeutic options, due to the low inherent capacity of RGCs to regenerate and due to the inhibitory milieu of the central nervous system. Among the numerous treatment approaches investigated to stimulate neuronal survival and axonal extension, cell transplantation emerges as a promising option. This review focuses on cell therapies with bone marrow mononuclear cells and bone marrow-derived mesenchymal stem cells, which have shown positive therapeutic effects in animal models of optic neuropathies. Different aspects of available preclinical studies are analyzed, including cell distribution, potential doses, routes of administration, and mechanisms of action. Finally, published and ongoing clinical trials are summarized.

scholarly journals Review of Preclinical and Clinical Studies of Bone Marrow-Derived Cell Therapies for Intracerebral Hemorrhage

2016 ◽  
Vol 2016 ◽  
pp. 1-18 ◽  
Author(s):  
Paulo Henrique Rosado-de-Castro ◽  
Felipe Gonçalves de Carvalho ◽  
Gabriel Rodriguez de Freitas ◽  
Rosalia Mendez-Otero ◽  
Pedro Moreno Pimentel-Coelho
Keyword(s):  
Bone Marrow ◽  
Intracerebral Hemorrhage ◽  
Clinical Studies ◽  
Hemorrhagic Stroke ◽  
Mononuclear Cells ◽  
Time Window ◽  
Therapeutic Potential ◽  
Cell Therapies ◽  
Life Years ◽  
Bone Marrow Derived Cells

Stroke is the second leading cause of mortality worldwide, causing millions of deaths annually, and is also a major cause of disability-adjusted life years. Hemorrhagic stroke accounts for approximately 10 to 27% of all cases and has a fatality rate of about 50% in the first 30 days, with limited treatment possibilities. In the past two decades, the therapeutic potential of bone marrow-derived cells (particularly mesenchymal stem cells and mononuclear cells) has been intensively investigated in preclinical models of different neurological diseases, including models of intracerebral hemorrhage and subarachnoid hemorrhage. More recently, clinical studies, most of them small, unblinded, and nonrandomized, have suggested that the therapy with bone marrow-derived cells is safe and feasible in patients with ischemic or hemorrhagic stroke. This review discusses the available evidence on the use of bone marrow-derived cells to treat hemorrhagic strokes. Distinctive properties of animal studies are analyzed, including study design, cell dose, administration route, therapeutic time window, and possible mechanisms of action. Furthermore, clinical trials are also reviewed and discussed, with the objective of improving future studies in the field.

scholarly journals Cell Therapies under Clinical Trials and Polarized Cell Therapies in Pre-Clinical Studies to Treat Ischemic Stroke and Neurological Diseases: A Literature Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6194 ◽  
Author(s):  
Masahiro Hatakeyama ◽  
Itaru Ninomiya ◽  
Yutaka Otsu ◽  
Kaoru Omae ◽  
Yasuko Kimura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Ischemic Stroke ◽  
Clinical Studies ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Functional Independence ◽  
Therapeutic Effects ◽  
Cell Therapies ◽  
Neuronal Stem Cells

Stroke remains a major cause of serious disability because the brain has a limited capacity to regenerate. In the last two decades, therapies for stroke have dramatically changed. However, half of the patients cannot achieve functional independence after treatment. Presently, cell-based therapies are being investigated to improve functional outcomes. This review aims to describe conventional cell therapies under clinical trial and outline the novel concept of polarized cell therapies based on protective cell phenotypes, which are currently in pre-clinical studies, to facilitate functional recovery after post-reperfusion treatment in patients with ischemic stroke. In particular, non-neuronal stem cells, such as bone marrow-derived mesenchymal stem/stromal cells and mononuclear cells, confer no risk of tumorigenesis and are safe because they do not induce rejection and allergy; they also pose no ethical issues. Therefore, recent studies have focused on them as a cell source for cell therapies. Some clinical trials have shown beneficial therapeutic effects of bone marrow-derived cells in this regard, whereas others have shown no such effects. Therefore, more clinical trials must be performed to reach a conclusion. Polarized microglia or peripheral blood mononuclear cells might provide promising therapeutic strategies after stroke because they have pleiotropic effects. In traumatic injuries and neurodegenerative diseases, astrocytes, neutrophils, and T cells were polarized to the protective phenotype in pre-clinical studies. As such, they might be useful therapeutic targets. Polarized cell therapies are gaining attention in the treatment of stroke and neurological diseases.

scholarly journals Cell Replacement Therapy for Retinal and Optic Nerve Diseases: Cell Sources, Clinical Trials and Challenges

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 865
Author(s):  
Rosa M. Coco-Martin ◽  
Salvador Pastor-Idoate ◽  
Jose Carlos Pastor
Keyword(s):  
Stem Cells ◽  
Clinical Trials ◽  
Optic Nerve ◽  
Progenitor Cells ◽  
Pluripotent Stem Cells ◽  
Limbal Stem Cells ◽  
Term Survival ◽  
Cell Therapies ◽  
Optic Nerve Diseases ◽  
Cell Sources

The aim of this review was to provide an update on the potential of cell therapies to restore or replace damaged and/or lost cells in retinal degenerative and optic nerve diseases, describing the available cell sources and the challenges involved in such treatments when these techniques are applied in real clinical practice. Sources include human fetal retinal stem cells, allogenic cadaveric human cells, adult hippocampal neural stem cells, human CNS stem cells, ciliary pigmented epithelial cells, limbal stem cells, retinal progenitor cells (RPCs), human pluripotent stem cells (PSCs) (including both human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)) and mesenchymal stem cells (MSCs). Of these, RPCs, PSCs and MSCs have already entered early-stage clinical trials since they can all differentiate into RPE, photoreceptors or ganglion cells, and have demonstrated safety, while showing some indicators of efficacy. Stem/progenitor cell therapies for retinal diseases still have some drawbacks, such as the inhibition of proliferation and/or differentiation in vitro (with the exception of RPE) and the limited long-term survival and functioning of grafts in vivo. Some other issues remain to be solved concerning the clinical translation of cell-based therapy, including (1) the ability to enrich for specific retinal subtypes; (2) cell survival; (3) cell delivery, which may need to incorporate a scaffold to induce correct cell polarization, which increases the size of the retinotomy in surgery and, therefore, the chance of severe complications; (4) the need to induce a localized retinal detachment to perform the subretinal placement of the transplanted cell; (5) the evaluation of the risk of tumor formation caused by the undifferentiated stem cells and prolific progenitor cells. Despite these challenges, stem/progenitor cells represent the most promising strategy for retinal and optic nerve disease treatment in the near future, and therapeutics assisted by gene techniques, neuroprotective compounds and artificial devices can be applied to fulfil clinical needs.

scholarly journals Demyelination of the Optic Nerve: An Underlying Factor in Glaucoma?

2021 ◽  
Vol 13 ◽  
Author(s):  
Jingfei Xue ◽  
Yingting Zhu ◽  
Zhe Liu ◽  
Jicheng Lin ◽  
Yangjiani Li ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Inflammatory Responses ◽  
Clinical Symptoms ◽  
Ganglion Cells ◽  
Neuronal Degeneration ◽  
Retinal Ganglion ◽  
Progressive Degeneration ◽  
Treatment Plans ◽  
The Central Nervous System ◽  
The Relationship

Neurodegenerative disorders are characterized by typical neuronal degeneration and axonal loss in the central nervous system (CNS). Demyelination occurs when myelin or oligodendrocytes experience damage. Pathological changes in demyelination contribute to neurodegenerative diseases and worsen clinical symptoms during disease progression. Glaucoma is a neurodegenerative disease characterized by progressive degeneration of retinal ganglion cells (RGCs) and the optic nerve. Since it is not yet well understood, we hypothesized that demyelination could play a significant role in glaucoma. Therefore, this study started with the morphological and functional manifestations of demyelination in the CNS. Then, we discussed the main mechanisms of demyelination in terms of oxidative stress, mitochondrial damage, and immuno-inflammatory responses. Finally, we summarized the existing research on the relationship between optic nerve demyelination and glaucoma, aiming to inspire effective treatment plans for glaucoma in the future.

scholarly journals Clot-Derived Contaminants in Transplanted Bone Marrow Mononuclear Cells Impair the Therapeutic Effect in Stroke

Stroke ◽  
2019 ◽  
Vol 50 (10) ◽  
pp. 2883-2891 ◽  
Author(s):  
Yuka Okinaka ◽  
Akie Kikuchi-Taura ◽  
Yukiko Takeuchi ◽  
Yuko Ogawa ◽  
Johannes Boltze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Mononuclear Cells ◽  
Blood Clot ◽  
Experimental Stroke ◽  
Bone Marrow Mononuclear Cell ◽  
Therapeutic Effects ◽  
Beneficial Effects ◽  
Preclinical And Clinical Studies ◽  
Possible Cause

Background and Purpose— The beneficial effects of bone marrow mononuclear cell (BM-MNC) transplantation in preclinical experimental stroke have been reliably demonstrated. However, only overall modest effects in clinical trials were observed. We have investigated and reported a cause of the discrepancy between the preclinical and clinical studies. Methods— To investigate the possible cause of low efficacy of BM-MNC transplantation in experimental stroke, we have focused on blood clot formation, which is not uncommon in human bone marrow aspirates. To evaluate the effects of clot-derived contaminants in transplanted BM-MNC on stroke outcome, a murine stroke model was used. Results— We show that BM-MNC separated by an automatic cell isolator (Sepax2), which does not have the ability to remove clots, did not attenuate brain atrophy after stroke. In contrast, manually isolated, clot-free BM-MNC exerted therapeutic effects. Clot-derived contaminants were also transplanted intravenously to poststroke mice. We found that the transplanted contaminants were trapped at the peristroke area, which were associated with microglial/macrophage activation. Conclusions— Clot-derived contaminants in transplanted BM-MNC nullify therapeutic effects in experimental stroke. This may explain neutral results in clinical trials, especially in those using automated stem cell separators that lack the ability to remove clot-derived contaminants. Visual Overview— An online visual overview is available for this article.

scholarly journals Foveate vision in deep–sea teleosts: a comparison of primary visual and olfactory inputs

2000 ◽  
Vol 355 (1401) ◽  
pp. 1315-1320 ◽  
Author(s):  
Shaun P. Collin ◽  
Darren J. Lloyd ◽  
Hans–Joachim Wagner
Keyword(s):  
Optic Nerve ◽  
Deep Sea ◽  
Ganglion Cells ◽  
Relative Size ◽  
Olfactory Nerve ◽  
Resolving Power ◽  
Retinal Ganglion ◽  
Foveal Vision ◽  
Bias Ratio ◽  
The Central Nervous System

The relative importance of vision in a foveate group of alepocephalid teleosts is examined in the context of a deep–sea habitat beyond the penetration limits of sunlight. The large eyes of Conocara spp. possess deep convexiclivate foveae lined with Müller cells comprising radial shafts of intermediate filaments and horizontal processes. Photoreceptor cell (171.8 × 10 3 rods mm −2 ) and retinal ganglion cell (11.9 × 10 3 cells mm −2 ) densities peak within the foveal clivus and the perifoveal slopes, respectively, with a centro–peripheral gradient between 3:1 (photoreceptors) and over 20:1 (ganglion cells). The marked increase in retinal sampling localized in temporal retina, coupled with a high summation ratio (13:1), suggest that foveal vision optimizes both spatial resolving power and sensitivity in the binocular frontal visual field. The elongated optic nerve head is comprised of over 500 optic papillae, which join at the embryonic fissure to form a thin nervous sheet behind the eye. The optic nerve is divided into two axonal bundles; one receiving input from the fovea (only unmyelinated axons) and the other from non–specialized retinal regions (25% of axons are myelinated), both of which appear to be separated as they reach the visual centres of the central nervous system. Comparison of the number of primary (first–order) axonal pathways for the visual (a total of 63.4 × 10 6 rod photoreceptors) and olfactory (a total of 15.24 × 10 5 olfactory nerve axons) inputs shows a marked visual bias (ratio of 41:1). Coupled with the relative size of the optic tecta (44.0 mm 3 ) and olfactory bulbs (0.9 mm 3 ), vision appears to play a major role in the survival of these deep–sea teleosts and emphasizes that ecological and behavioural strategies account for significant variation in sensory brain structure.

scholarly journals The Therapeutic Effects after Transplantation of Whole-Layer Olfactory Mucosa in Rats with Optic Nerve Injury

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Shun Gong ◽  
Hai Jin ◽  
Danfeng Zhang ◽  
Wei Zou ◽  
Chunhui Wang ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Nerve Injury ◽  
Retinal Ganglion Cells ◽  
Ganglion Cells ◽  
Cell Types ◽  
Olfactory Mucosa ◽  
Therapeutic Effects ◽  
Retinal Ganglion ◽  
Optic Nerve Injury ◽  
The Right

Background. Existing evidence suggests the potential therapy of transplanting olfactory ensheathing cells (OEC) either alone or in combination with neurotrophic factors or other cell types in optic nerve injury (ONI). However, clinical use of autologous OEC in the acute stages of ONI is not possible. On the other hand, acute application of heterologous transplantation may bring the issue of immune rejection. The olfactory mucosa (OM) with OEC in the lamina propria layer is located in the upper region of the nasal cavity and is easy to dissect under nasal endoscopy, which makes it a candidate as autograft material in acute stages of ONI. To investigate the potential of the OM on the protection of injured neurons and on the promotion of axonal regeneration, we developed a transplantation of syngenic OM in rats with ONI model. Methods. After the right optic nerve was crushed in Lewis rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats undergoing phosphate buffered saline (PBS) injection were used as negative controls (NC). The authors evaluated the regeneration of retinal ganglion cells (RGCs) and axons for 3, 7, 14, and 28 days after transplantation. Obtained retinas and optic nerves were analyzed histologically. Results. Transplantations of OM significantly promoted the survival of retinal ganglion cells (RGCs) and axonal growth of RGCs compared with PBS alone. Moreover, OM group was associated with higher expression of GAP-43 in comparison with the PBS group. In addition to the potential effects on RGCs, transplantations of OM significantly decreased the expression of GFAP in the retinas, suggesting inhibiting astrocyte activation. Conclusions. Transplantation of whole-layer OM in rats contributes to the neuronal survival and axon regeneration after ONI.

scholarly journals Non-Cell-Autonomous Regulation of Optic Nerve Regeneration by Amacrine Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Elena G. Sergeeva ◽  
Paul A. Rosenberg ◽  
Larry I. Benowitz
Keyword(s):  
Optic Nerve ◽  
Visual Information ◽  
Ganglion Cells ◽  
Amacrine Cells ◽  
Inflammatory Cells ◽  
Retinal Ganglion ◽  
Ability To Regenerate ◽  
Mature Neurons ◽  
The Central Nervous System ◽  
Extracellular Environment

Visual information is conveyed from the eye to the brain through the axons of retinal ganglion cells (RGCs) that course through the optic nerve and synapse onto neurons in multiple subcortical visual relay areas. RGCs cannot regenerate their axons once they are damaged, similar to most mature neurons in the central nervous system (CNS), and soon undergo cell death. These phenomena of neurodegeneration and regenerative failure are widely viewed as being determined by cell-intrinsic mechanisms within RGCs or to be influenced by the extracellular environment, including glial or inflammatory cells. However, a new concept is emerging that the death or survival of RGCs and their ability to regenerate axons are also influenced by the complex circuitry of the retina and that the activation of a multicellular signaling cascade involving changes in inhibitory interneurons – the amacrine cells (AC) – contributes to the fate of RGCs. Here, we review our current understanding of the role that interneurons play in cell survival and axon regeneration after optic nerve injury.

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