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Bone marrow-derived mononuclear stem cells in the treatment of retinal degenerations

Neural Regeneration Research 2022年第9期17卷 1937-1944页

作者： Diego García-Ayuso Johnny Di Pierdomenico David García-Bernal Manuel Vidal-Sanz María P.Villegas-Pérez Departamento de Oftalmología Facultad de MedicinaUniversidad de MurciaCampus de Ciencias de la saludMurciaSpain Instituto Murciano de Investigación Biosanitaria Hospital Virgen de la Arrixaca(IMIB-Virgen de la Arrixaca) MurciaSpain Servicio de Hematología Hospital Clínico Universitario Virgen de la ArrixacaMurciaSpain

Retinal degenerative diseases affecting the outer retina in its many forms(inherited,acquired or induced)are characterized by photoreceptor loss,and represent currently a leading cause of irreversible vision loss in the world.At present,there are very few treatments capable of preventing,recovering or reversing photoreceptor degeneration or the secondary retinal remodeling,which follows photoreceptor loss and can also cause the death of other retinal cells.Thus,these diseases are nowadays one of the greatest challenges in the field of ophthalmological research.Bone marrow derived-mononuclear stem cell transplantation has shown promising results for the treatment of photoreceptor degenerations.These cells may have the potential to slow down photoreceptor loss,and therefore should be applied in the early stages of photoreceptor degenerations.Furthermore,because of their possible paracrine effects,they may have a wide range of clinical applications,since they can potentially impact on several retinal cell types at once and photoreceptor degenerations can involve different cells and/or begin in one cell type and then affect adjacent cells.The intraocular injection of bone marrow derived-mononuclear stem cells also enhances the outcomes of other treatments aimed to protect photoreceptors.Therefore,it is likely that future investigations may combine bone marrow derived-mononuclear stem cell therapy with other systemic or intraocular treatments to obtain greater therapeutic effects in degenerative retinal diseases.

关键词： age-related macular degeneration bone marrow stem cells intravitreal injection macroglia microglia photoreceptor degeneration retinal ganglion cells retinitis pigmentosa subretinal injection transplant

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Mechanisms implicated in the contralateral effect in the central nervous system after unilateral injury:focus on the visual system

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Neural Regeneration Research 2021年第11期16卷 2125-2131页

作者： Fernando Lucas-Ruiz Caridad Galindo-Romero Virginia Albaladejo-García Manuel Vidal-Sanz Marta Agudo-Barriuso Departamento de Oftalmología Facultad de MedicinaUniversidad de Murcia and Instituto Murciano de Investigación Biosanitaria-Virgen de la Arrixaca(IMIBArrixaca)MurciaSpain

The retina,as part of the central nervous system is an ideal model to study the response of neurons to injury and disease and to test new treatments.During the last decade is becoming clear that unilateral lesions in bilateral areas of the central nervous system trigger an inflammatory response in the contralateral uninjured site.This effect has been better studied in the visual system where,as a rule,one retina is used as experimental and the other as control.Contralateral retinas in unilateral models of retinal injury show neuronal degeneration and glial activation.The mechanisms by which this adverse response in the central nervous system occurs are discussed in this review,focusing primarily on the visual system.

关键词： bilateral effect brain glaucoma inflammation mirror effect optic nerve axotomy optic nerve crush retina spinal cord

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Pan-retinal ganglion cell markers in mice, rats, and rhesus macaques

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Zoological Research 2023年第1期44卷 226-248页

作者： Francisco M.Nadal-Nicolás Caridad Galindo-Romero Fernando Lucas-Ruiz Nicholas Marsh-Amstrong Wei Li Manuel Vidal-Sanz Marta Agudo-Barriuso Grupo de Oftalmología Experimental Instituto Murciano de Investigación Biosanitaria Pascual Parrilla(IMIB)Murcia 30120Spain Dpto.Oftalmología Facultad de MedicinaUniversidad de MurciaMurcia 30120Spain Retinal Neurophysiology Section National Eye InstituteNational Institutes of HealthBethesdaMaryland 20892-2510USA Department of Ophthalmology and Vision Science University of CaliforniaDavisCA 95817USA

Univocal identification of retinal ganglion cells(RGCs) is an essential prerequisite for studying their degeneration and neuroprotection. Before the advent of phenotypic markers, RGCs were normally identified using retrograde tracing of retinorecipient areas. This is an invasive technique, and its use is precluded in higher mammals such as monkeys. In the past decade, several RGC markers have been described. Here, we reviewed and analyzed the specificity of nine markers used to identify all or most RGCs, i.e., pan-RGC markers, in rats, mice, and macaques. The best markers in the three species in terms of specificity, proportion of RGCs labeled, and indicators of viability were BRN3A, expressed by vision-forming RGCs, and RBPMS, expressed by vision-and non-vision-forming RGCs. NEUN, often used to identify RGCs, was expressed by non-RGCs in the ganglion cell layer, and therefore was not RGC-specific. γ-SYN, TUJ1, and NF-L labeled the RGC axons, which impaired the detection of their somas in the central retina but would be good for studying RGC morphology. In rats, TUJ1 and NF-L were also expressed by non-RGCs. BM88, ERRβ,and PGP9.5 are rarely used as markers, but they identified most RGCs in the rats and macaques and ERRβ in mice. However, PGP9.5 was also expressed by non-RGCs in rats and macaques and BM88 and ERRβ were not suitable markers of viability.

关键词： RGC Optic nerve crush BM88 BRN3A Estrogen-related receptorβ ERRβ NEUN Neurofilament-L PGP9.5 RBPMS γ-SYN βIII-tubulin TUJ1

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Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

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Neural Regeneration Research 2024年第3期19卷 542-547页

作者： María Norte-Muñoz David García-Bernal Diego García-Ayuso Manuel Vidal-Sanz Marta Agudo-Barriuso Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la Salud30120 MurciaSpain Grupo de Investigación Trasplante Hematopoyético y Terapia celular Departamento de Bioquímica e Inmunología.Facultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la Salud30120 MurciaSpain

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

关键词： adaptive immunity cell therapy central nervous system immune system innate immunity mesenchymal stromal cells neuroregeneration preclinical studies retina transplantation

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Role of microglial cells in photoreceptor degeneration

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Neural Regeneration Research 2019年第7期14卷 1186-1190页

作者： Johnny Di Pierdomenico Diego García-Ayuso Marta Agudo-Barriuso Manuel Vidal-Sanz María Paz Villegas-Pérez Departamento de Oftalmología Facultad de MedicinaUniversidad de Murciaand Instituto Murciano de Investigación Biosanitaria Hospital Virgen de la Arrixaca(IMIB-Virgen de la Arrixaca)

Inherited photoreceptor degeneration in humans constitutes a major cause of irreversible blindness in the world.They comprise various diseases,but retinitis pigmentosa is the most frequently observed.Retinitis pigmentosa is commonly limited to the eye,where there is progressive photoreceptor degeneration,rods and secondarily cones.The mechanisms of cone and rod degeneration continue to be investigated,since most of the mutations causing retinitis pigmentosa affect rods and thus,the secondary death of cones is an intriguing question but,ultimately,the cause of blindness.Understanding the mechanisms of rod and cone degeneration could help us to develop therapies to stop or,at least,slow down the degeneration process.Secondary cone degeneration has been attributed to the trophic dependence between rods and cones,but microglial cell activation could also have a role.In this review,based on previous work carried out in our laboratory in early stages of photoreceptor degeneration in two animal models of retinitis pigmentosa,we show that microglial cell activation is observed prior to the the initiation of photoreceptor death.We also show that there is an increase of the retinal microglial cell densities and invasion of the outer retinal layers by microglial cells.The inhibition of the microglial cells improves photoreceptor survival and morphology,documenting a role for microglial cells in photoreceptor degeneration.Furthermore,these results indicate that the modulation of microglial cell reactivity can be used to prevent or diminish photoreceptor death in inherited photoreceptor degenerations.

关键词： Royal College of Surgeons RCS P23H-1 microglia minocycline photoreceptor retinal degeneration retinitis pigmentosa

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Intravitreal fluorogold tracing as a method to label retinal neurons and the retinal pigment epithelium

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Neural Regeneration Research 2021年第10期16卷 2000-2001页

作者： Francisco Javier Valiente-Soriano Fernando Lucas-Ruiz Juan A.Miralles de Imperial-Ollero Manuel Vidal-Sanz Marta Agudo-Barriuso Departamento de Oftalmología Facultad de MedicinaUniversidad de Murcia and Instituto Murciano de Investigación Biosanitaria-Virgen de la Arrixaca(IMIB-Arrixaca)MurciaSpain

Techniques to label the neuroretina and the retinal pigment epithelium(RPE)have been the topic of many studies for years.The reliability and reproducibility of these techniques are essential to investigate retinal alterations of ocular pathologies and possible treatments.In particular,the study of the integrity of the RPE is of great importance in pathologies such as retinitis pigmentosa or age-related macular degeneration(Gu et al.,2012;Fisher and Ferrington,2018;Zhang et al.,2019).The most common approaches use antibodies to identify different cell populations.Recently,we have described a novel technique to study the integrity of the neuroretina and the RPE,as well as the functionality of the RPE in rats(Valiente-Soriano et al.,2020).

关键词： epithelium al. alterations

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Retinal remodeling following photoreceptor degeneration causes retinal ganglion cell death

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Neural Regeneration Research 2018年第11期13卷 1885-1886页

作者： Diego Garcia-Ayuso Johnny Di Pierdomenico Marta Agudo-Barriuso Manuel Vidal-Sanz Maria P. ViUegas-Perez Departamento de Oftalmologla Facultad de Medicina Universidad de Murcia and Instituto Murciano de Investigacion Biosanitaria Hospital Virgen de la Arrixaca (IMIB-Virgen de la Arrixaca) Murcia Spain

The retina is the extension of the central nervous system that senses light.Cones and rods,situated in the outer retina,convert light into electrical signals that travel through intermediate neurons where these are fu... 详细信息

关键词： COMPRESSION VESSELS

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Taurine: a promising nutraceutic in the prevention of retinal degeneration

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Neural Regeneration Research 2024年第3期19卷 606-610页

作者： Diego García-Ayuso Johnny Di Pierdomenico Ana Martínez-Vacas Manuel Vidal-Sanz Serge Picaud María PVillegas-Pérez Grupo de Investigación Oftalmología Experimental Departamento de OftalmologíaOptometríaOtorrinolaringología y Anatomía PatológicaFacultad de MedicinaUniversidad de MurciaInstituto Murciano de Investigación Biosanitaria(IMIB)Campus de Ciencias de la SaludMurciaEspaña Sorbonne Université INSERMCNRSInstitut de la VisionParisFrance

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

关键词： amino acid anti-inflammatory antioxidant gamma-aminobutyric acid nutraceutical photoreceptor degeneration retina retinitis pigmentosa taurine

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Melanopsin expression is an indicator of the well-being of melanopsin-expressing retinal ganglion cells but not of their viability

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Neural Regeneration Research 2016年第8期11卷 1243-1244页

作者： Marta Agudo-Barriuso Francisco M.Nadal-Nicolás María H.Madeira Giuseppe Rovere Beatriz vidal-Villegas Manuel Vidal-Sanz Departamento de Oftalmologia Facultad de Medicina Universidad de Murcia and Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca) Murcia Spain Institute for Biomedical Imaging and Life Sciences (IBILI) Faculty of Medicine University of Coimbra Coimbra Portugal CNC.IBILI University of Coimbra Coimbra Portugal

Light is an electromagnetic stimulus that in mammals is sensed by specialized neurons in the retina.The physiological response to light encompasses two fundamental and different functional outputs：image-forming and n... 详细信息

关键词： RGCs retina specialized physiological expressing ganglion viability tracing Figure unpublished

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Mesenchymal stromal cell therapy for damaged retinal ganglion cells, is gold all that glitters?

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Neural Regeneration Research 2019年第11期14卷 1851-1857页

作者： Fernando Lucas-Ruiz Caridad Galindo-Romero David García-Bernal María Norte-Munoz Kristy T. Rodríguez-Ramírez manuel Salinas-Navarro Jose E. Millán-Rivero Manuel Vidal-Sanz Marta Agudo-Barriuso Grupo de Oftalmologia Experimental Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca)MurciaSpain Department of Talmologia Universidad de MurciaMurciaSpain Unidad de Terapia Celular y Trasplante Hematopoyetico Instituto Murciano de Investigacion Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca)MurciaSpain Department of Medicina Interna Universidad de MurciaMurciaSpain

Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical models, it has been shown that mesenchymal stromal cells have neuroprotective and immunomodulatory properties, both of which are ideal for central nervous system treatment and repair. Here we will review the current literature on mesenchymal stromal cells, focusing on bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and mesenchymal stromal cells from the umbilical cord stroma, i.e.,Wharton’s jelly mesenchymal stromal cells. Finally, we will discuss the use of these cells to alleviate retinal ganglion cell degeneration following axonal trauma.

关键词： stem cells adipose stem cells umbilical cord bone marrow Wharton's jelly optic nerve axotomy neuroprotection

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