• Diabetes mellitus
• diabetes complications
• embryonic stem.
• mesenchymal stem cells
• reprogramming
• stem cells therapy

• Humans
• Diabetes Complications/therapy
• Stem Cell Transplantation
• Cellular Reprogramming
• Animals
• Diabetes Mellitus/therapy
• Induced Pluripotent Stem Cells
• Insulin-Secreting Cells

• Autologous
• Bone marrow
• Diabetes complications
• Mesenchymal stem cells
• Mononuclear cells
• Type 2 diabetes mellitus

• Humans
• Diabetes Mellitus, Type 2/therapy
• Male
• Female
• Mesenchymal Stem Cell Transplantation/methods
• Middle Aged
• Follow-Up Studies
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/cytology
• Leukocytes, Mononuclear/metabolism
• Aged
• C-Peptide/metabolism
• C-Peptide/blood
• Adult
• Combined Modality Therapy

• Eye diseases
• mesenchymal stem cells
• regeneration
• stem cells

• Cell therapy
• MSCs
• Retinal Disease
• hESCs
• iPSCs

• Humans
• Retina
• Macular Degeneration/therapy
• Visual Acuity
• Cell- and Tissue-Based Therapy

• Animal models
• Good manufacturing practice
• Retinal degeneration
• Retinitis pigmentosa
• Stem/neural progenitor cells
• Toxicology study

• Humans
• Animals
• Rats
• Swine
• Swine, Miniature
• Retinal Degeneration/therapy
• Retinitis Pigmentosa
• Neurons
• Ambulatory Care Facilities

• California Institute for Regenerative Medicine

• Automation
• mouse
• optometry
• optomotor response
• visual acuity
• visual performance

• Mice
• Animals
• Evoked Potentials, Visual
• Mice, Inbred C57BL
• Visual Acuity
• Rodentia

• Humans
• Chemotaxis
• Stem Cell Transplantation
• Chemokine CXCL12/genetics

• diabetes
• immunomodulation
• mesenchymal stem cells
• regeneration

• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells
• Immunomodulation
• Cell Differentiation
• Diabetes Mellitus/therapy
• Diabetes Mellitus/metabolism
• Fibrosis

Retinal diseases are major causes of irreversible vision loss and blindness. Despite extensive research into their pathophysiology and etiology, pharmacotherapy effectiveness and surgical outcomes remain poor. Based largely on numerous preclinical studies, administration of mesenchymal stem cells (MSCs) as a therapeutic strategy for retinal diseases holds great promise, and various approaches have been applied to the therapies. However, hindered by the retinal barriers, the initial vision for the stem cell replacement strategy fails to achieve the anticipated effect and has now been questioned. Accumulating evidence now suggests that the paracrine effect may play a dominant role in MSC-based treatment, and MSC-derived extracellular vesicles emerge as a novel compelling alternative for cell-free therapy. This review summarizes the therapeutic potential and current strategies of this fascinating class of cells in retinal degeneration and other retinal dysfunctions.

• Humans
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/physiology
• Extracellular Vesicles
• Retinal Diseases/therapy
• Cell- and Tissue-Based Therapy

Vigabatrin (VGB) is an effective antiepileptic drug used mainly to treat infantile spasms and refractory complex partial seizures. However, using VGB was restricted as it was known to cause retinal toxicity that appears as a severe peripheral visual field defect. Accordingly, this study was conducted to examine the histopathological and biochemical effects of VGB on the retina in adult male albino rats and assess the possible therapeutic role of mesenchymal stem cells (MSCs) against this potential toxicity. The rats were divided into three groups (control group, VGB group, and VGB/MSCs group), one week after 65 days of VGB treatment ±MSCs. The right eyeballs were prepared for histological and immunohistochemical examination, whereas the left eyeballs were prepared for real-time polymerase chain reaction analysis. Our results demonstrated that MSCs ameliorated retinal pathological changes and downregulated the expression of glial fibrillary acidic protein, vascular endothelial growth factor, and synaptophysin after VGB administration suggesting MSCs function and vascular modulating effect. Moreover, MSCs regulate retinal tissue gene expression of BAX, Bcl-2, BDNF, NGF, synapsin, interleukin (IL)-6, IL-1β, and occludin suggesting MSCs antiapoptotic and immunomodulating effect. In conclusion, MSCs administration could be a suitable therapeutic line to ameliorate VGB-induced retinopathy.

• Brain-derived neurotrophic factor
• Nerve growth factor
• Retina
• Synapsins
• Synaptophysin

• P23H-1
• RCS
• bone marrow mononuclear stem cell
• glial cells
• photoreceptors
• retinitis pigmentosa

Retinitis pigmentosa (RP) consists of a group of inherited, retinal degenerative disorders and is characterized by progressive loss of rod photoreceptors and eventual degeneration of cones in advanced stages, resulting in vision loss or blindness. Gene therapy has been effective in treating autosomal recessive RP (arRP). However, limited options are available for patients with autosomal dominant RP (adRP). In vivo gene editing may be a therapeutic option to treat adRP. We previously rescued vision in neonatal adRP rats by the selective ablation of the Rhodopsin S334ter transgene following electroporation of a CRISPR/Cas9 vector. However, the translational feasibility and long-term safety and efficacy of ablation therapy is unclear. To this end, we show that AAV delivery of a CRISPR/Cas9 construct disrupted the Rhodopsin P23H transgene in postnatal rats, which rescued long-term vision and retinal morphology.

• EY026743 NIH HHS

Currently, there is no treatment for retinal degenerative diseases (RDD) such as retinitis pigmentosa (RP). Stem cell-based therapies could provide promising opportunities to repair the damaged retina and restore vision. Thus far, primarily adult mesenchymal stem cells (MSCs) have been investigated in preclinical and clinical studies, and the results have not been convincing. We applied a new approach in which primitive (p) MSC-derived retinal progenitor cells (RPCs) were examined to treat retinal degeneration in an rd12 mouse model of RP.

Well-characterized pMSCs and RPCs labeled with PKH26 were intravitreally injected into rd12 mice. The vision and retinal function of transplanted animals were analyzed using electroretinography. Animals were killed 4 and 8 weeks after cell transplantation for histological, immunological, molecular, and transcriptomic analyses of the retina.

Transplanted RPCs significantly improved vision and retinal thickness as well as function in rd12 mice. pMSCs and RPCs homed to distinct retinal layers. pMSCs homed to the retinal pigment epithelium, and RPCs migrated to the neural layers of the retina, where they improved the thickness of the respective layers and expressed cell-specific markers. RPCs induced anti-inflammatory and neuroprotective responses as well as upregulated the expression of genes involved in neurogenesis. The transcriptomic analysis showed that RPCs promoted neurogenesis and functional recovery of the retina through inhibition of BMP and activation of JAK/STAT and MAPK signaling pathways.

Our study demonstrated that RPCs countered inflammation, provided retinal protection, and promoted neurogenesis resulting in improved retinal structure and physiological function in rd12 mice.

The online version contains supplementary material available at 10.1186/s13287-022-02828-w.

• Neurogenesis
• Neuroprotection
• Retinal degenerative diseases
• Retinal progenitor cells
• Retinitis pigmentosa

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.

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

Human umbilical cord mesenchymal stem cells (UCMSCs) transplantation is a promising therapy for the treatment of retinitis pigmentosa (RP). However, intravenously infused cells may be blocked in the lung, increasing the risk of vascular obstruction, which needs to be optimized to further improve safety and efficacy.

We derived small UCMSCs (S-UCMSCs) from filtering UCMSCs with a 10-μm filter, and compared with UCMSCs by flow cytometry, directional differentiation culture and transcriptome sequencing. Then the S-UCMSCs and UCMSCs were intravenously infused in the Royal College Surgeons (RCS) rats to evaluate the safety and the efficacy.

The diameter of S-UCMSCs ranged from 5.568 to 17.231 μm, with an average diameter of 8.636 ± 2.256 μm, which was significantly smaller than that of UCMSCs. Flow cytometry, immunofluorescence and transcriptome sequencing demonstrated that the S-UCMSCs and UCMSCs were the same kind of MSCs, and the S-UCMSCs were more proliferative. After the S-UCMSCs and UCMSCs were intravenously infused into the Royal College of Surgeons (RCS) rats at a dose of 1 × 10⁶ cells/rat, the S-UCMSCs blocked in the lungs were significantly fewer and disappeared more quickly than UCMSCs. The b wave of the flash electroretinogram was improved at 7 d, and the retinal outer nuclear layer thickness was thicker at 7 d and 14 d. The expression level of inflammation was inhibited, and the expression level of neurotrophic factors was upregulated in the retina and serum after transplantation.

S-UCMSCs intravenous infusion was safer than UCMSCs and could delay retinal degeneration and protect visual function in RCS rats, which may be a preferable therapeutic approach for RP.

The online version contains supplementary material available at 10.1186/s12886-021-02171-3.

• Efficacy
• Intravenous infusion
• Retinitis pigmentosa
• Safety
• Umbilical cord mesenchymal stem cells

• Cell therapy
• Gene therapy
• Nutritional therapy
• Retinitis pigmentosa
• Stem cell transplantation

• ESC-RPE
• Retinal degenerative disease
• age-related macular degeneration (AMD)
• iPSC-RPE
• retinal progenitor cells
• retinitis pigmentosa (RP)
• stem cell therapy

Retinitis pigmentosa (RP) is a hereditary retinal degenerative disease leading to eventual blindness. When RP is combined with macular edema (ME), the visual impairment further worsens. We compared a modified sub-Tenon’s capsule injection of triamcinolone acetonide (TA) and the intravenous infusion of umbilical cord mesenchymal stem cells (UCMSCs) in the treatment of RP combined with ME (RP-ME) to assess their safety and efficacy in eliminating ME and restoring visual function. A phase I/II clinical trial enrolled 20 patients was conducted. All patients were followed up for 6 months. There were no severe adverse effects in both groups. In retinal morphological tests, the central macular thickness (CMT) in TA group significantly decreased at first week, first and second month after injection (p < 0.05). The CMT in UCMSCs group significantly decreased at first month after infusion. The rate of reduction of CMT in TA group was significantly greater than that in UCMSCs group at second month (p < 0.05). Reversely, the rate of reduction of CMT in UCMSCs group was significantly greater than that in TA group at sixth month (p < 0.05). In visual functional test, although there were no significant differences in visual acuity or visual fields within each group or between groups, but the amplitude of P2 wave of flash visual evoked potential (FVEP) showed significant increasing in TA group at second month in UCMSCs group at sixth month (p < 0.05). At 6th month, the rate of growth in the amplitude of P2 wave in USMCSs group was significantly greater than that in TA group (p < 0.05). This study suggests both modified sub-Tenon’s capsule injection of TA and intravenous infusion of UCMSCs are safe for RP-ME patients. TA injection is more effective at alleviating ME while improving visual function in a short term. UCMSC intravenous infusion shows slow but persistent action in alleviating ME, and can improve the visual function for a longer time. These approaches can be applied separately or jointly depending on the disease condition for patients to benefit maximumly.

Clinical Trial Registration:http://www.chictr.org.cn, identifier ChiCTR-ONC-16008839

• macular edema
• retinitis pigmentosa
• sub-Tenon’s capsule injection
• triamcinolone acetonide
• umbilical cord mesenchymal stem cells

• Diabetic retinopathy
• Eye diseases
• Glaucoma
• Mesenchymal stem cells
• Regenerative medicine
• Retinitis pigmentosa

Inherited photoreceptor degenerations are not treatable diseases and a frequent cause of blindness in working ages. In this study we investigate the safety, integration and possible rescue effects of intravitreal and subretinal transplantation of adult human bone-marrow-derived mononuclear stem cells (hBM-MSCs) in two animal models of inherited photoreceptor degeneration, the P23H-1 and the Royal College of Surgeons (RCS) rat. Immunosuppression was started one day before the injection and continued through the study. The hBM-MSCs were injected in the left eyes and the animals were processed 7, 15, 30 or 60 days later. The retinas were cross-sectioned, and L- and S- cones, microglia, astrocytes and Müller cells were immunodetected. Transplantations had no local adverse effects and the CD45+ cells remained for up to 15 days forming clusters in the vitreous and/or a 2–3-cells-thick layer in the subretinal space after intravitreal or subretinal injections, respectively. We did not observe increased photoreceptor survival nor decreased microglial cell numbers in the injected left eyes. However, the injected eyes showed decreased GFAP immunoreactivity. We conclude that intravitreal or subretinal injection of hBM-MSCs in dystrophic P23H-1 and RCS rats causes a decrease in retinal gliosis but does not have photoreceptor neuroprotective effects, at least in the short term. However, this treatment may have a potential therapeutic effect that merits further investigation.

• inherited photoreceptor degeneration
• intravitreal transplant
• subretinal transplant

• intravenous infusion
• retinitis pigmentosa
• umbilical cord mesenchymal stem cell
• visual function

• Batch Cell Culture Techniques/methods
• Betacoronavirus
• Bioreactors
• COVID-19
• Coronavirus Infections/therapy
• Coronavirus Infections/virology
• Graft vs Host Disease/therapy
• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Metabolic Engineering/methods
• Pandemics
• Pneumonia, Viral/therapy
• Pneumonia, Viral/virology
• SARS-CoV-2
• Transplant Recipients

• HL095722 NIH HHS
• NS107857 NIH HHS
• National Institutes of Health
• King Abdulaziz City for Science and Technology

• Blood–retinal barrier
• Graft survival
• Interleukin-13
• Mesenchymal stem cell
• Microglia
• Subretinal transplantation

• Animals
• Genetic Therapy/methods
• Graft Survival
• Interleukin-13/genetics
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/metabolism
• Microglia
• Nerve Growth Factors/metabolism
• Rats
• Rats, Sprague-Dawley
• Retinal Degeneration/genetics
• Retinal Degeneration/surgery

• 2016QH041 Startup Fund for scientific research of Fujian Medical University
• JT180188 Fund for Young and Middle-aged University Teachers' educational research of Fujian Province
• Startup Fund for scientific research of Fujian Medical University

Retinal degeneration causes irreversible blindness. Human retinal progenitor cells (hRPCs) have the potential to treat retinal diseases. The vitreous cavity is a relatively immune-privileged site that is suitable for stem cell transplantation in the treatment of retinal diseases. This study aimed to evaluate the therapeutic efficacy and safety of intravitreal injection of hRPCs in retinal degeneration therapy.

hRPCs were primary-cultured and injected into the vitreous cavity of RCS rats. To determine whether hRPCs formed teratomas in immune-deficient mice, hRPCs at different passages were transplanted into BALB/c-nu mice. The visual function was detected by electroretinography recording. Changes in the outer nuclear layer (ONL) were analyzed by histological testing and cell counting. The protective mechanism was further assessed by cytokine antibody array.

Intravitreal transplantation of hRPCs maintained retinal function and preserved retinal morphology. Importantly, grafted cells in the vitreous cavity were well tolerated, with no adverse effects. Teratoma was not formed in BALB/c-nu mice after hRPCs transplantation. The number of hRPCs-injected eyes and thickness of ONL in the hRPCs-treated group were higher than those in the untreated group and HBSS injection group. The cytokine antibody array revealed that hRPCs expressed GDF-15, PDGF-AA, EGF, and NT-4.

Our findings show that intravitreal injection of hRPCs is effective and safe in protecting photoreceptor cells in RCS rats, but were no longer effective at 12 weeks after transplantation. Moreover, hRPCs released multiple neurotrophic factors that may be involved in treating retinal disease.

Our study aimed to evaluate the protective role and mechanisms of bone marrow mesenchymal stem cells (BMSCs) in hypoxic photoreceptors and experimental retinal detachment. The cellular morphology, viability, apoptosis and autophagy of hypoxic 661w cells and cells cocultured with BMSCs were analysed. In retinal detachment model, BMSCs were intraocularly transplanted, and then, the retinal morphology, outer nuclear layer (ONL) thickness and rhodopsin expression were studied as well as apoptosis and autophagy of the retinal cells. The hypoxia‐induced apoptosis of 661w cells obviously increased together with autophagy levels increasing and peaking at 8 hours after hypoxia. Upon coculturing with BMSCs, hypoxic 661w cells had a better morphology and fewer apoptosis. After autophagy was inhibited, the apoptotic 661w cells under the hypoxia increased, and the cell viability was reduced, even in the presence of transplanted BMSCs. In retina‐detached eyes transplanted with BMSCs, the retinal ONL thickness was closer to that of the normal retina. After transplantation, apoptosis decreased significantly and retinal autophagy was activated in the BMSC‐treated retinas. Increased autophagy in the early stage could facilitate the survival of 661w cells under hypoxic stress. Coculturing with BMSCs protects 661w cells from hypoxic damage, possibly due to autophagy activation. In retinal detachment models, BMSC transplantation can significantly reduce photoreceptor cell death and preserve retinal structure. The capacity of BMSCs to reduce retinal cell apoptosis and to initiate autophagy shortly after transplantation may facilitate the survival of retinal cells in the low‐oxygen and nutrition‐restricted milieu after retinal detachment.

• apoptosis
• autophagy
• bone marrow mesenchymal stem cells
• hypoxia
• photoreceptor cell damage
• retinal detachment

• Dominant Optic Atrophy (DOA)
• Kjers Optic Neuropathy
• bone marrow derived stem cells (BMSC)
• stem cells
• visual loss

Retinal degenerative disorders, such as diabetic retinopathy, retinitis pigmentosa, age-related macular degeneration or glaucoma, represent the most common causes of loss of vision and blindness. In spite of intensive research, treatment options to prevent, stop or cure these diseases are limited. Newer therapeutic approaches are offered by stem cell-based therapy. To date, various types of stem cells have been evaluated in a range of models. Among them, mesenchymal stem/stromal cells (MSCs) derived from bone marrow or adipose tissue and used as autologous cells have been proposed to have the potential to attenuate the negative manifestations of retinal diseases. MSCs delivered to the vicinity of the diseased retina can exert local anti-inflammatory and repair-promoting/regenerative effects on retinal cells. However, MSCs also produce numerous factors that could have negative impacts on retinal regeneration. The secretory activity of MSCs is strongly influenced by the cytokine environment. Therefore, the interactions among the molecules produced by the diseased retina, cytokines secreted by inflammatory cells and factors produced by MSCs will decide the development and propagation of retinal diseases. Here we discuss the interactions among cytokines and other factors in the environment of the diseased retina treated by MSCs, and we present results supporting immunoregulatory and trophic roles of molecules secreted in the vicinity of the retina during MSC-based therapy.

• Retina
• Degenerative diseases
• Stem cell therapy
• Mesenchymal stem cells
• Cytokines
• Growth factors

• Clinical trial
• Cornea
• Eye disorders
• Mesenchymal stem cells
• Ophthalmology
• Retina

• MSCs
• Stargardt disease
• cone-rod dystrophies
• macular degeneration
• mesenchymal stem cells
• ophthalmic diseases
• optic nerve atrophy
• retinal degeneration
• stem cell therapy

• Mouse models
• Neurodegeneration
• Neuromuscular disease
• Neuroscience

This study aimed to investigate whether the transplantation of genetically engineered bone marrow-derived mesenchymal stromal cells (MSCs) to overexpress brain-derived neurotrophic factor (BDNF) could rescue the chronic degenerative process of slow retinal degeneration in the rd6 (retinal degeneration 6) mouse model and sought to identify the potential underlying mechanisms. Rd6 mice were subjected to the intravitreal injection of lentivirally modified MSC-BDNF or unmodified MSC or saline. In vivo morphology, electrophysiological retinal function (ERG), and the expression of apoptosis-related genes, as well as BDNF and its receptor (TrkB), were assessed in retinas collected at 28 days and three months after transplantation. We observed that cells survived for at least three months after transplantation. MSC-BDNF preferentially integrated into the outer retinal layers and considerably rescued damaged retinal cells, as evaluated by ERG and immunofluorescence staining. Additionally, compared with controls, the therapy with MSC-BDNF was associated with the induction of molecular changes related to anti-apoptotic signaling. In conclusion, BDNF overexpression observed in retinas after MSC-BDNF treatment could enhance the neuroprotective properties of transplanted autologous MSCs alone in the chronically degenerated retina. This research provides evidence for the long-term efficacy of genetically-modified MSC and may represent a strategy for treating various forms of degenerative retinopathies in the future.

• BDNF
• MSC
• OCT
• lentiviral vectors
• rd6
• regenerative medicine
• retinal degeneration
• tissue imaging

• Blue-light (BL)
• Bone marrow mesenchymal stem cells (BMSCs)
• Ciliary neurotrophic factor (CNTF)
• Retinal pigment epithelium (RPE)

• Interleukin-6
• adipose tissue-derived stem cells
• ciliary neurotrophic factor (CNTF)
• mesenchymal stem cells
• retinal degeneration
• transplantation

• Adipose Tissue/cytology
• Animals
• Cells, Cultured
• Ciliary Neurotrophic Factor/metabolism
• Disease Models, Animal
• Injections, Intraperitoneal
• Interleukin-6/blood
• Interleukin-6/metabolism
• Intravitreal Injections
• Iodates
• Lipopolysaccharides/pharmacology
• Mice, Inbred C57BL
• Protective Agents/metabolism
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Rats
• Retinal Degeneration/blood
• Retinal Degeneration/genetics
• Retinal Degeneration/pathology
• Retinal Degeneration/therapy
• Retinal Pigment Epithelium/pathology
• Stem Cell Transplantation
• Stem Cells/cytology
• Up-Regulation

• Animals
• Cell Lineage
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/physiopathology
• Diabetes Mellitus, Type 2/therapy
• Diabetic Angiopathies/etiology
• Diabetic Cardiomyopathies/physiopathology
• Diabetic Cardiomyopathies/therapy
• Diabetic Retinopathy/physiopathology
• Diabetic Retinopathy/therapy
• Humans
• Hyperglycemia/complications
• Insulin/metabolism
• Insulin Resistance
• Mice
• Microcirculation
• Nitrosative Stress
• Oxidative Stress
• Signal Transduction
• Stem Cell Transplantation
• Stem Cells/cytology
• Wound Healing

The Royal College of Surgeons (RCS) rat gradually loses vision due to retinal degeneration. Previous physiological studies have depicted the progressive loss of optical responses in the visual pathway, including the primary visual cortex (V1), over the course of retinal degeneration in the RCS rat. However, little is known about how the excitability of the V1 circuit changes during over the course of the gradual loss of visual signal input from the retina. We elucidated the properties of responses to electrical stimulations directly applied to V1 at different stages of vision input loss in the RCS rat in reference to those of the Long-Evans (LE) rat, using in vivo voltage-sensitive dye imaging. The V1 neuronal network of the RCS rat exhibited an excitatory response comparable to the LE rat. The excitatory response was maintained even long after total loss of the visual signal input from the retina. However, the response time-course suggested that the suppressive response was somewhat debilitated in the RCS rat. This is the first experiment demonstrating the long-term effect of retinal degeneration on cortical activities. Our findings provide the physiological fundamentals to enhance the preclinical research of cortical prostheses with the use of the RCS rat.

Age-related macular degeneration (AMD) leads to progressive loss of central vision in the elderly. At a cellular level, there is aging of the retinal pigment epithelial (RPE) cells, and accumulation of lipofuscin that interferes with the proper functioning of RPE which eventually leads to apoptosis. Treatment depends on the stage of the disease. Wet AMD which has neovascularization is managed by local therapies such as laser photocoagulation and photodynamic therapy and is managed with injections of antivascular endothelial growth factor-based therapy. Unlike the wet AMD, an effective therapy does not exist for dry AMD and geographic atrophy. Cell replacement therapy has shown promise. This review discusses the opportunities in the various types of cell-based therapy, their limitations, and what is possible for India.

Dysfunction and death of retinal pigment epithelium (RPE) and or photoreceptors can lead to irreversible vision loss. The eye represents an ideal microenvironment for stem cell-based therapy. It is considered an “immune privileged” site, and the number of cells needed for therapy is relatively low for the area of focused vision (macula). Further, surgical placement of stem cell-derived grafts (RPE, retinal progenitors, and photoreceptor precursors) into the vitreous cavity or subretinal space has been well established. For preclinical tests, assessments of stem cell-derived graft survival and functionality are conducted in animal models by various noninvasive approaches and imaging modalities. In vivo experiments conducted in animal models based on replacing photoreceptors and/or RPE cells have shown survival and functionality of the transplanted cells, rescue of the host retina, and improvement of visual function. Based on the positive results obtained from these animal experiments, human clinical trials are being initiated. Despite such progress in stem cell research, ethical, regulatory, safety, and technical difficulties still remain a challenge for the transformation of this technique into a standard clinical approach. In this review, the current status of preclinical safety and efficacy studies for retinal cell replacement therapies conducted in animal models will be discussed.

Blood-brain barrier impairment is a major indicator of endothelial dysfunction in diabetes. Studies showed that endothelial progenitor cell (EPC) transplantation promoted angiogenesis and improved function recovery after hind limb ischemia in diabetic mice. The effect of EPC transplantation on blood-brain barrier integrity after cerebral ischemia in diabetic animals is unknown. The aim of this study is to explore the effect of EPC transplantation on the integrity of the blood-brain barrier after cerebral ischemia in diabetic mice.

EPCs were isolated by density gradient centrifugation and characterized by flow cytometry and immunostaining. Diabetes was induced in adult male C57BL/6 mice by a single injection of streptozotocin at 4 weeks before surgery. Diabetic mice underwent 90-minute transient middle cerebral artery occlusion surgery and received 1 × 10⁶ EPCs transplantation immediately after reperfusion. Brain infarct volume, blood-brain barrier permeability, tight junction protein expression, and hypoxia inducible factor-1α (HIF-1α) mRNA level were examined after treatment.

We demonstrated that neurological deficits were attenuated and brain infarct volume was reduced in EPC-transplanted diabetic mice after transient cerebral ischemia compared to the controls (p < 0.05). Blood-brain barrier leakage and tight junction protein degradation were reduced in EPC-transplanted mice (p <0.05). EPCs upregulated HIF-1α expression while HIF-1α inhibitor PX-478 abolished the beneficial effect of EPCs.

We conclude that EPCs protected blood-brain barrier integrity after focal ischemia in diabetic mice through upregulation of HIF-1α signaling.

• Blood-brain barrier
• Diabetes
• Endothelial progenitor cell
• HIF-1α
• Ischemic stroke

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

• Induced pluripotent stem cell
• neovascular age-related macular degeneration
• non-neovascular age-related macular degeneration
• stem cell

• 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

• Bone marrow
• CD34
• Hematopoietic
• Mesenchymal
• Retina
• Stem cells

• Animals
• Bone Marrow Cells/classification
• Humans
• Mesenchymal Stem Cells/cytology
• Retinal Diseases/surgery
• Stem Cell Transplantation/methods

• R01 EY026556 NEI NIH HHS
• T32 HL086350 NHLBI NIH HHS
• P30 EY012576 NEI NIH HHS
• UL1 TR001860 NCATS NIH HHS
• R01 GM099688 NIGMS NIH HHS
• R01 EY024239 NEI NIH HHS

• CRISPR/Cas9
• Epsins
• Genome Editing Technology
• Retinal Degeneration
• VEGFR2 Signaling

• R01 HL133216 NHLBI NIH HHS
• SC1 DK104821 NIDDK NIH HHS
• SC1 CA200517 NCI NIH HHS
• R01 HL137229 NHLBI NIH HHS
• P20 RR018758 NCRR NIH HHS
• R01 HL093242 NHLBI NIH HHS
• R01 HL118676 NHLBI NIH HHS
• R01 HL130845 NHLBI NIH HHS

• In vitro
• In vivo
• MSCs
• Retinal differentiation
• Transplantation

• Age-related macular degeneration
• Immunosuppression
• Mesenchymal stem cell transplantation
• Retinal pigment epithelium
• Retinitis pigmentosa
• Stromal derived factor-1α
• Translational research
• Trophic factor receptors

• Animals
• Cell Movement
• Cell Separation
• Cells, Cultured
• Chemokine CXCL12/metabolism
• Disease Models, Animal
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/physiology
• Paracrine Communication
• Phagocytosis
• Photoreceptor Cells, Vertebrate/metabolism
• Photoreceptor Cells, Vertebrate/pathology
• Rats
• Retina/metabolism
• Retina/pathology
• Retina/physiopathology
• Retinal Dystrophies/metabolism
• Retinal Dystrophies/pathology
• Retinal Dystrophies/physiopathology
• Retinal Dystrophies/prevention & control
• Retinal Pigment Epithelium/metabolism
• Retinal Pigment Epithelium/pathology
• Signal Transduction
• Time Factors
• Transplantation, Isogeneic
• Vision Disorders/metabolism
• Vision Disorders/pathology
• Vision Disorders/physiopathology
• Vision Disorders/prevention & control
• Vision, Ocular

• Endothelial progenitor cells
• IL-10
• Inflammation
• Nonproliferative diabetic retinopathy
• Vascular repair