• Clinical trials
• Regeneration
• Retinal cells
• Retinal degeneration
• Stem cell therapy
• Transplantation

• Humans
• Retinal Degeneration/therapy
• Retinal Degeneration/pathology
• Stem Cell Transplantation
• Animals
• Stem Cells/cytology
• Cell- and Tissue-Based Therapy/methods
• Retina/cytology
• Retina/pathology

• 82172882 National Natural Science Foundation of China
• 82101143 National Natural Science Foundation of China
• LZ24H120003 Zhejiang Provincial Natural Science
• LQ24C120003 Zhejiang Provincial Natural Science

• human embryonic stem cells
• neural progenitors
• retinal degeneration
• transplanted cell survival in rodents

• CiteSpace
• VOSviewer
• bibliometric analysis
• glaucoma
• hotspots
• stem cells
• trend
• visualization

• Brain
• HIV
• HIV-1 comorbidities
• Pericytes

• Humans
• HIV-1
• Endothelial Cells
• HIV Infections

• F31 NS125905 NINDS NIH HHS
• R01 DA050528 NIDA NIH HHS
• R21 MH122235 NIMH NIH HHS
• National Institute on Drug Abuse
• National Institute of Neurological Disorders and Stroke
• National Institute of Mental Health

• AMD, Age-related macular degeneration
• BDNF, Brain derived neurotrophic factor
• CNTF, Ciliary neurotrophic factor
• GDNF, Glial‐derived neurotrophic factor
• Glaucoma
• IOP, Intraocular pressure
• LoGTS, Low-Pressure Glaucoma Treatment Study
• MRI, Magnetic resonance imaging
• MSCs, Mesenchymal stem cells
• NGF, Nerve growth factor
• NTG, Normal tension glaucoma
• OCTA, Optical coherence tomography angiography
• PBM, hotobiomodulation
• PDGF, Platelet derived growth factor
• POAG, Primary open angle glaucoma
• RGCs, Retinal ganglion cells
• TNF-α, Tumor necrosis factor- α
• bFGF, Basic fibroblast growth factor
• gene therapy
• intracranial pressure
• intraocular pressure
• neuroprotection
• ocular blood flow
• oxidative stress
• retinal ganglion cells
• stem cell therapy

• Antibiotics
• Antiglaucomatous agents
• Cell-based therapy
• Dietary supplementation
• Electrical stimulation therapy
• Gene therapy
• Glaucoma
• Neuroprotection
• Neurotrophic factors
• Novel neuroprotective molecules

• Mesenchymal stem cells
• NMDA
• cell therapy
• chemokine receptors
• chemokines
• photoreceptors
• retina degeneration
• retina regeneration
• retinal gabglion cells
• retinitis pigmentosa

• Glaucoma
• Regeneration
• Retinal ganglion cells
• Stem cells
• Transplantation

• optic nerve
• neuro-protection
• neuro-regeneration
• retinal ganglion cell
• stem cell
• neurotrophins

• Animals
• Axons/physiology
• Humans
• Nerve Regeneration/physiology
• Neuroprotection/physiology
• Optic Nerve/physiopathology
• Optic Nerve Diseases/physiopathology
• Optic Nerve Diseases/therapy
• Optic Nerve Injuries/physiopathology
• Optic Nerve Injuries/therapy

• P30 EY029220 NEI NIH HHS
• UL1 TR001855 NCATS NIH HHS

• Age-related macular degeneration (AMD)
• Induced pluripotent stem cells (iPSCs)
• Photoreceptors
• Retinal degenerative disease
• Retinal pigment epithelium (RPE)

Degenerative retinal disease leads to significant visual morbidity worldwide. Diabetic retinopathy and macular degeneration are leading causes of blindness in the developed world. While current therapies for these diseases slow disease progression, stem cell and gene therapy may also reverse the effects of these, and other, degenerative retinal conditions. Novel therapies being investigated include the use of various types of stem cells in the regeneration of atrophic or damaged retinal tissue, the prolonged administration of neurotrophic factors and/or drug delivery, immunomodulation, as well as the replacement of mutant genes, and immunomodulation through viral vector delivery. This review will update the reader on aspects of stem cell and gene therapy in diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa and other less common inherited retinal dystrophies. These therapies include the use of adeno-associated viral vector-based therapies for treatment of various types of retinitis pigmentosa and dry age-related macular degeneration. Other potential therapies reviewed include the use of mesenchymal stem cells in local immunomodulation, and the use of stem cells in generating structures like three-dimensional retinal sheets for transplantation into degenerative retinas. Finally, aspects of stem cell and gene therapy in diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, and other less common inherited retinal dystrophies will be reviewed.

Sight is a major sense for human and visual impairment profoundly affects quality of life, especially retinal degenerative diseases which are the leading cause of irreversible blindness worldwide. As for other neurodegenerative disorders, almost all retinal dystrophies are characterized by the specific loss of one or two cell types, such as retinal ganglion cells, photoreceptor cells, or retinal pigmented epithelial cells. This feature is a critical point when dealing with cell replacement strategies considering that the preservation of other cell types and retinal circuitry is a prerequisite. Retinal ganglion cells are particularly vulnerable to degenerative process and glaucoma, the most common optic neuropathy, is a frequent retinal dystrophy. Cell replacement has been proposed as a potential approach to take on the challenge of visual restoration, but its application to optic neuropathies is particularly challenging. Many obstacles need to be overcome before any clinical application. Beyond their survival and differentiation, engrafted cells have to reconnect with both upstream synaptic retinal cell partners and specific targets in the brain. To date, reconnection of retinal ganglion cells with distal central targets appears unrealistic since central nervous system is refractory to regenerative processes. Significant progress on the understanding of molecular mechanisms that prevent central nervous system regeneration offer hope to overcome this obstacle in the future. At the same time, emergence of reprogramming of human somatic cells into pluripotent stem cells has facilitated both the generation of new source of cells with therapeutic potential and the development of innovative methods for the generation of transplantable cells. In this review, we discuss the feasibility of stem cell-based strategies applied to retinal ganglion cells and optic nerve impairment. We present the different strategies for the generation, characterization and the delivery of transplantable retinal ganglion cells derived from pluripotent stem cells. The relevance of pluripotent stem cell-derived retinal organoid and retinal ganglion cells for disease modeling or drug screening will be also introduced in the context of optic neuropathies.

• cell transplantation
• disease modeling
• glaucoma
• human iPSCs
• retinal ganglion cells (RGCs)

• Batten disease
• cell therapy
• clinical trials
• gene therapy
• lysosomal storage disease
• neuronal ceroid lipofuscinosis

• FLIO
• fluorescence lifetime imaging
• retinitis pigmentosa

• P30 EY014800 NEI NIH HHS
• R01 EY011600 NEI NIH HHS
• R29 EY011600 NEI NIH HHS

Stem cells are undifferentiated cells which have the ability to self-renew and differentiate into mature cells. They are highly proliferative, implying that an unlimited number of mature cells can be generated from a given stem cell source. On this basis, stem cell replacement therapy has been evaluated in recent years as an alternative for various pathologies. Degenerative retinal diseases cause progressive visual decline which originates from continuing loss of photoreceptor cells and outer nuclear layers. Theoretically, this therapy will enable the generation of new retinal cells from stem cells to replace the damaged cells in the diseased retina. In addition, stem cells are able to perform multiple functions, such as immunoregulation, anti-apoptosis of neurons, and neurotrophin secretion. With recent progress in experimental stem cell applications, phase I/II clinical trials have been approved. These latest stem cell transplantation studies showed that this therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa, Stargardts’ macular dystrophy, and age-related macular degeneration. This review focuses on new developments in stem cell therapy for degenerative retinal diseases.

• Stem cell
• recent developments
• retinal diseases

Retinal degenerative diseases, which lead to the death of rod and cone photoreceptor cells, are the leading cause of inherited vision loss worldwide. Induced pluripotent or embryonic stem cells (iPSCs/ESCs) have been proposed as a possible source of new photoreceptors to restore vision in these conditions. The proof of concept studies carried out in mouse models of retinal degeneration over the past decade have highlighted several limitations for cell replacement in the retina, such as the low efficiency of cone photoreceptor production from stem cell cultures and the poor integration of grafted cells in the host retina. Current protocols to generate photoreceptors from stem cells are largely based on the use of extracellular factors. Although these factors are essential to induce the retinal progenitor cell (RPC) fate from iPSCs/ESCs, developmental studies have shown that RPCs alter fate output as a function of time (i.e., their temporal identity) to generate the seven major classes of retinal cell types, rather than spatial position. Surprisingly, current stem cell differentiation protocols largely ignore the intrinsic temporal identity of dividing RPCs, which we argue likely explains the low efficiency of cone production in such cultures. In this article, we briefly review the mechanisms regulating temporal identity in RPCs and discuss how they could be exploited to improve cone photoreceptor production for cell replacement therapies.

• cell replacement therapies
• cone photoreceptors
• neural progenitors
• retinal degenerative diseases
• stem cells
• temporal identity

• Age-related Macular Degeneration (AMD)
• Induced Pluripotent Stem Cells (iPSCs)
• Mesenchymal Stem Cells (MSCs)
• Photoreceptors
• Retinal ganglion cells (RGCs)
• Retinal pigment epithelium (RPE)

Retinal degeneration (RD), such as age-related macular degeneration (AMD) and retinitis pigmentosa, is one of the leading causes of blindness. Presently, no satisfactory therapeutic options are available for these diseases principally because the retina and retinal pigmented epithelium (RPE) do not regenerate, although wet AMD can be prevented from further progression by anti-vascular endothelial growth factor therapy. Nevertheless, stem/progenitor cell approaches exhibit enormous potential for RD treatment using strategies mainly aimed at the rescue and replacement of photoreceptors and RPE. The sources of stem/progenitor cells are classified into two broad categories in this review, which are (1) ocular-derived progenitor cells, such as retinal progenitor cells, and (2) non-ocular-derived stem cells, including embryonic stem cells, induced pluripotent stem cells, and mesenchymal stromal cells. Here, we discuss in detail the progress in the study of four predominant stem/progenitor cell types used in animal models of RD. A short overview of clinical trials involving the stem/progenitor cells is also presented. Currently, stem/progenitor cell therapies for RD still have some drawbacks such as inhibited proliferation and/or differentiation in vitro (with the exception of the RPE) and limited long-term survival and function of grafts in vivo. Despite these challenges, stem/progenitor cells represent the most promising strategy for RD treatment in the near future.

• Clinical trials
• Differentiation
• Proliferation
• Retinal degeneration
• Stem/progenitor cells
• Transplantation

• Age-related macular degeneration
• Animal models
• Retinitis pigmentosa
• Stem cell therapy
• Transplantation
• Visual function

• Animals
• Cell- and Tissue-Based Therapy/methods
• Humans
• Practice Guidelines as Topic
• Retinal Degeneration/physiopathology
• Retinal Degeneration/therapy
• Visual Acuity

• R01 EY020488 NEI NIH HHS

A major cause of visual disorders is dysfunction and/or loss of the light-sensitive cells of the retina, the photoreceptors. To develop better treatments for patients, we need to understand how inherited retinal disease mutations result in the dysfunction of photoreceptors. New advances in the field of stem cell and gene editing research offer novel ways to model retinal dystrophies in vitro and present opportunities to translate basic biological insights into therapies.

This brief review will discuss some of the issues that should be taken into account when carrying out disease modelling and gene editing of retinal cells. We will discuss (i) the use of human induced pluripotent stem cells (iPSCs) for disease modelling and cell therapy; (ii) the importance of using isogenic iPSC lines as controls; (iii) CRISPR/Cas9 gene editing of iPSCs; and (iv) in vivo gene editing using AAV vectors.

Ground-breaking advances in differentiation of iPSCs into retinal organoids and methods to derive mature light sensitive photoreceptors from iPSCs. Furthermore, single AAV systems for in vivo gene editing have been developed which makes retinal in vivo gene editing therapy a real prospect.

Genome editing is becoming a valuable tool for disease modelling and in vivo gene editing in the retina.

• Disease modelling
• Gene editing
• Induced pluripotent stem cells
• Photoreceptors
• Retina
• Vision impairment

• Animals
• Cell Differentiation
• Cell- and Tissue-Based Therapy/methods
• Humans
• Retinal Degeneration/therapy
• Retinal Ganglion Cells/cytology
• Signal Transduction
• Stem Cell Transplantation
• Stem Cells/cytology

• Autologous, therapy
• Intravitreal implantation
• Lysosomal storage disease
• Mesenchymal stem cells
• Retinal degeneration
• Trophic effects

Deafferentation results not only in sensory loss, but also in a variety of alterations in the postsynaptic circuitry. These alterations may have detrimental impact on potential treatment strategies. Progressive loss of photoreceptors in retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to several changes in the remnant retinal circuitry. Müller glial cells undergo hypertrophy and form a glial seal. The second- and third-order retinal neurons undergo morphological, biochemical and physiological alterations. A result of these alterations is that retinal ganglion cells (RGCs), the output neurons of the retina, become hyperactive and exhibit spontaneous, oscillatory bursts of spikes. This aberrant electrical activity degrades the signal-to-noise ratio in RGC responses, and thus the quality of information they transmit to the brain. These changes in the remnant retina, collectively termed “retinal remodeling”, pose challenges for genetic, cellular and bionic approaches to restore vision. It is therefore crucial to understand the nature of retinal remodeling, how it affects the ability of remnant retina to respond to novel therapeutic strategies, and how to ameliorate its effects. In this article, we discuss these topics, and suggest that the pathological state of the retinal output following photoreceptor loss is reversible, and therefore, amenable to restorative strategies.

• optogenetics
• oscillatory activity
• retinal degeneration
• retinal prostheses
• stem cells

• Decellularization
• Extracellular matrix (ECM)
• Retina
• Retinal progenitor cell (RPC)
• Tissue engineering

Glaucoma is the second leading cause of blindness worldwide and is most notably characterized by progressive optic nerve atrophy and advancing loss of retinal ganglion cells (RGCs). The main concomitant factor is the elevated intraocular pressure (IOP). Existing treatments are focused generally on lowering IOP. However, both RGC loss and optic nerve atrophy can independently occur with IOP at normal levels. In recent years, there has been substantial progress in the development of neuroprotective therapies for glaucoma in order to restore vital visual function. The present review intends to offer a brief insight into conventional glaucoma treatments and discuss exciting current developments of mostly preclinical data in novel neuroprotective strategies for glaucoma that include recent advances in noninvasive diagnostics going beyond IOP maintenance for an enhanced global view. Such strategies now target RGC loss and optic nerve damage, opening a critical therapeutic window for preventative monitoring and treatment.

• glaucoma
• neuroprotection
• retinal ganglion cell

A sustained intraocular administration of neurotrophic factors is among the strategies aimed at establishing treatments for currently untreatable degenerative retinal disorders. In the present study we have analyzed the neuroprotective effects of a continuous neural stem (NS) cell-based intraocular delivery of ciliary neurotrophic factor (CNTF) on photoreceptor cells in the nclf mouse, an animal model of the neurodegenerative lysosomal storage disorder variant late infantile neuronal ceroid lipofuscinosis (vLINCL). To this aim, we genetically modified adherently cultivated NS cells with a polycistronic lentiviral vector encoding a secretable variant of CNTF together with a Venus reporter gene (CNTF-NS cells). NS cells for control experiments (control-NS cells) were modified with a vector encoding the reporter gene tdTomato. Clonal CNTF-NS and control-NS cell lines were established using fluorescent activated cell sorting and intravitreally grafted into 14 days old nclf mice at the onset of retinal degeneration. The grafted cells preferentially differentiated into astrocytes that were attached to the posterior side of the lenses and the vitreal side of the retinas and stably expressed the transgenes for at least six weeks, the latest post-transplantation time point analyzed. Integration of donor cells into host retinas, ongoing proliferation of grafted cells or adverse effects of the donor cells on the morphology of the host eyes were not observed. Quantitative analyses of host retinas two, four and six weeks after cell transplantation revealed the presence of significantly more photoreceptor cells in eyes with grafted CNTF-NS cells than in eyes with grafted control-NS cells. This is the first demonstration that a continuous intraocular administration of a neurotrophic factor attenuates retinal degeneration in an animal model of neuronal ceroid lipofuscinosis.

• Animals
• Cell Count
• Cell Line
• Ciliary Neurotrophic Factor/genetics
• Ciliary Neurotrophic Factor/therapeutic use
• Clone Cells
• Disease Models, Animal
• Gene Expression
• Genes, Reporter
• Genetic Therapy
• Genetic Vectors/metabolism
• Immunoblotting
• Injections, Intraocular
• Intravitreal Injections
• Lentivirus/genetics
• Mice, Inbred C57BL
• Neural Stem Cells/cytology
• Neural Stem Cells/metabolism
• Neural Stem Cells/transplantation
• Neuronal Ceroid-Lipofuscinoses/pathology
• Neuronal Ceroid-Lipofuscinoses/therapy
• Photoreceptor Cells/metabolism
• Photoreceptor Cells/pathology
• Retinal Degeneration/therapy
• Stem Cell Transplantation

Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue in vitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although iPS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-based therapy for ocular diseases.

• Microenvironment
• Niche
• Stem cell
• Cell-based therapy
• Ocular diseases
• Ophthalmology

Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment.

• Bone marrow-derived stem cells
• CD34(+)CD38(+)
• CD34(+)CD38(−)
• Differentiation
• Human
• In vitro
• Retinal pigment epithelial cells

• cytokines
• mesenchymal stromal cells
• neuroprotection
• ocular hypertension
• retinal ganglion cells

• Adipose Tissue/cytology
• Animals
• Bone Marrow Cells/cytology
• Bone Marrow Cells/drug effects
• Cell Count
• Cell Differentiation/drug effects
• Cell Separation
• Cells, Cultured
• Cytokines/metabolism
• Disease Models, Animal
• Female
• Flow Cytometry
• Green Fluorescent Proteins/metabolism
• Immunohistochemistry
• Intraocular Pressure/drug effects
• Intravitreal Injections
• Male
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Neuroprotective Agents/administration & dosage
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Ocular Hypertension/drug therapy
• Ocular Hypertension/physiopathology
• Ocular Hypertension/therapy
• Rats, Wistar
• Retinal Ganglion Cells/drug effects
• Retinal Ganglion Cells/pathology

Introduction: Retinitis pigmentosa (RP), an inherited disease characterized by progressive loss of photoreceptors and retinal pigment epithelium, is a leading genetic cause of blindness. Cell transplantation to replace lost photoreceptors is a potential therapeutic strategy, but technical limitations have prevented clinical application. Adult human peripheral blood mononuclear cells (hPBMCs) may be an ideal cell source for such therapies. This study examined the survival and migration of pre-induced hPBMCs three months after subretinal transplantation in the retinal degeneration slow (rds) mouse model of RP. Materials and Methods: Freshly isolated adult hPBMCs were pre-induced by co-culture with neonatal Sprague-Dawley (SD) rat retinal tissue for 4 days in neural stem cell medium. Pre-induced cells were labeled with CM-DiI for tracing and injected into the right subretinal space of rds mice by the trans-scleral approach. After two and three months, right eyes were harvested and transplanted cell survival and migration examined in frozen sections and whole mountretinas. Immunofluorescence in whole-mount retinas was used to detect the expression of human neuronal and photorece ptorsprotein markers by transplanted cells. Results: Pre-induced adult hPBMCs could survive in vivo and migrate to various parts of the retina. After two and three months, transplanted cells were observed in the ciliary body, retinal outer nuclear layer, inner nuclear layer, ganglion cell layer, optic papilla, and within the optic nerve. The neuronal and photoreceptor markers CD90/Thy1, MAP-2, nestin, and rhodopsin were expressed by subpopulations of CM-DiI-positive cells three months after subretinal transplantation. Conclusion: Pre-induced adult hPBMCs survived for at least three months after subretinal transplantation, migrated throughout the retina, and expressed human protein markers. These results suggest that hPBMCs could be used for cell replacement therapy to treat retinal degenerative diseases.

The central nervous system is vulnerable to many neurodegenerative disorders such as Alzheimer's disease that result in the extensive loss of neuronal cells. Stem cells have the ability to differentiate into many types of cells, which make them ideal for treating such disorders. Although stem cell therapy has shown some promising results in animal models for many brain disorders it has yet to translate into the clinic. A major hurdle to the translation of stem cell therapy into the clinic is the immune response faced by stem cell transplants. Here, we focus on immunological and related hurdles to stem cell therapies for central nervous system disorders.

• Glial cells
• Neurodegeneration
• Neuroprotection
• Retinal diseases
• Retinal remodeling
• Retinal therapy

• Anti-Inflammatory Agents/therapeutic use
• Antioxidants/therapeutic use
• Apoptosis/physiology
• Clinical Trials as Topic
• Humans
• Neurodegenerative Diseases/physiopathology
• Neurodegenerative Diseases/therapy
• Neuroprotective Agents/therapeutic use
• Oxidative Stress/physiology
• Retinal Degeneration/physiopathology
• Retinal Degeneration/therapy
• Retinal Neurons/pathology
• Retinal Neurons/physiology
• Stem Cell Transplantation/methods

• glaucoma
• neuroprotection
• retinal ganglion cell
• stem cell
• trabecular meshwork

• Endothelial progenitor cell transplantation
• Monocyte derived macrophages
• Neurovascular protection
• Residual microglia

Purpose. The purpose of this work was to evaluate the retinal integration and differentiation of neurospheres formed by stem cells and mouse neural progenitor cells injected intravitreally in mice eyes with retinal injury. Methods. Eight male C57BL mice, 8 weeks old, were submitted to intraperitoneal injection of sodium iodate (2% NaIO3, 50 mg/kg). After 72 hours, 2 μL of solution with mNPC were injected intravitreally (100.000 cells/μL). After 7 days, their eyes were dissected and cryoprotected in 30% sucrose in PB for at least 24 hours at 4°C. The material was analyzed by immunohistochemistry and the following primary antibodies evaluation. Results. The results showed that the grafted cells integrated and survived in the adult mice within the sinner retinal tissue for at least 7 days. Immunohistochemical analysis revealed mature neuronal pattern in some regions. The mNPC population in the transplants was tightly surrounded by neuroretinal cells, suggesting their active role in neuron survival. Notably, the appearance of GFP-positive mNPC was not the result of fusion between donor cells and endogenous neuroretinal cells. Conclusions. Migration, survival, and differentiation of mNPCs were observed after 7 days following a single application with neurosphere method. The results may be clinically relevant for future stem cell therapy to restore retinal degeneration.

• regeneration
• stem cell
• tissue engineering

• Ciliary neurotrophic factor
• Lentiviral vector
• Neural stem cell
• Retinal photoreceptors
• Stem cell transplantation

• Animals
• Cells, Cultured
• Ciliary Neurotrophic Factor/genetics
• Ciliary Neurotrophic Factor/metabolism
• Cyclic Nucleotide Phosphodiesterases, Type 6/genetics
• Disease Models, Animal
• Genetic Therapy
• Genetic Vectors
• Lentivirus/genetics
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Mutation
• Neural Stem Cells/metabolism
• Neural Stem Cells/transplantation
• Neurogenesis
• Photoreceptor Cells, Vertebrate/metabolism
• Retina/metabolism
• Retina/pathology
• Retinitis Pigmentosa/genetics
• Retinitis Pigmentosa/metabolism
• Retinitis Pigmentosa/pathology
• Retinitis Pigmentosa/therapy
• Spheroids, Cellular
• Transduction, Genetic
• Transfection

• Animals
• Cell Differentiation
• Cell Movement
• Cell Survival
• Cells, Cultured
• Culture Media, Conditioned
• Cytoprotection
• Evoked Potentials, Visual
• Humans
• Induced Pluripotent Stem Cells/physiology
• Male
• Nerve Growth Factors/metabolism
• Nerve Regeneration
• Neural Stem Cells/physiology
• Neural Stem Cells/transplantation
• Optic Nerve/pathology
• Optic Nerve/physiopathology
• Optic Nerve Injuries/physiopathology
• Optic Nerve Injuries/therapy
• Rats
• Retinal Ganglion Cells/pathology

• RPE
• embryonic stem cells
• eye development
• human ES cells
• photoreceptors
• retinal differentiation
• transplantation

• age-related macular degeneration
• rpe
• stem cells

• Disease Progression
• Embryonic Stem Cells/cytology
• Humans
• Macular Degeneration/etiology
• Macular Degeneration/physiopathology
• Macular Degeneration/therapy
• Models, Theoretical
• Pluripotent Stem Cells/cytology
• Retinal Pigment Epithelium/cytology
• Stem Cell Transplantation