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Temporal and spatial course of photoreceptor loss after light exposure. Hematoxylin and eosin–stained retinal cross-sections of control retinas (lower row) and of the left (dilated) eyes from animals photoexposed under circular (left two columns) or linear (right two columns) bulbs. Images were taken from the mid-dorsal and midventral retina. A-D: animals processed at 0 h, E-H: 7 days, I-L: 1 month, M-P: 3 months, Q: 6 months, R, S: 9 months, T: 12 months after light exposure (ALE) and control animals. U-V represents control animals. Photoreceptor loss is observed in all sections but in D (animals processed 0 h ALE; ventral retina), where the retinal structure is conserved and is similar to control animals. Photoreceptor loss was always more severe in the dorsal retina. During the first 3 months ALE, retinal damage was more drastic in the animals exposed to circular bulbs; however, from this time point onwards, it was similar in all animals (M-P). Six or more months ALE (Q-T), vascular complexes (arrowheads) were observed in the subretinal space, sometimes connected to vessels that ran vertically in the retina and that are surrounded by nonpigmented cells (arrows). The scale bar represents 100 µm.
Source publication
To analyze the damage produced by light in mydriatic and miotic albino retinas under two different sources of light.
Albino Sprague Dawley female rats were exposed to 3,000 lx during 48 h under two different light sources: linear and circular bulbs. Before exposure, their left pupils were dilated. Before and at different times after light exposure...
Citations
... RGC axons form the optic nerve and therefore most models of RGC degeneration involve optic nerve injury (Vidal-Sanz et al., 2017), either direct (optic nerve crush or transection) or indirect (ocular hypertension models). Photoreceptor degeneration models include induced (García-Ayuso et al., 2011;Reisenhofer et al., 2017) or hereditary (García-Ayuso et al., 2010 models. ...
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.
... RGC axons form the optic nerve and therefore most models of RGC degeneration involve optic nerve injury (Vidal-Sanz et al., 2017), either direct (optic nerve crush or transection) or indirect (ocular hypertension models). Photoreceptor degeneration models include induced (García-Ayuso et al., 2011;Reisenhofer et al., 2017) or hereditary (García-Ayuso et al., 2010 models. ...
Many preclinical studies using adult Mesenchymal Stromal Cells (MSCs) for neurodegenerative diseases show promising results. However, there is a lack of concordance between the extensive research on MSC neuroprotection and clinical translation as evidenced by the few clinical trials currently using this strategy. A major discordance between animal models and patients is the type of transplant. Commonly, human cells are tested in animal models but this is a xenotransplant. As a rule, though, patients are either treated with autologous (syngeneic) or allogeneic cells. However, the crosstalk between the grafted cells and the host tissue is something that, despite its importance, is not being systematically investigated. We will show here that the therapeutic outcome, host homeostasis and immune response to intravitreal administered bone‐marrow MSCs radically changes depending on the type of transplantation. As expected, xenografts are the more damaging, followed by allografts with or without immunosuppression. Syngrafts are not completely innocuous, but they do not alter neuronal functionality, making them the safest and the best ones to neuroprotect and to induce axonal regeneration. In conclusion, the transplantation modality should be taken into consideration when conducting preclinical studies if we intend a more realistic translation into clinical practice.
... The mechanical pressure on the retina is alleviated upon SO removal, helping assess SVD and SPD. Secondly, eyes with SO are very vulnerable to a transient increase in light exposure, which might cause retinal thinning and vascular insufficiency [28,29]. We infer that, upon SO removal, the threshold for phototoxicity might be restored. ...
Background
This study evaluated the vascular changes in the macular and peripapillary regions before and after silicone oil (SO) removal in patients with rhegmatogenous retinal detachment.
Methods
This single-center case series assessed patients who underwent SO removal at one hospital. Patients who underwent pars plana vitrectomy and perfluoropropane gas tamponade (PPV + C3F8) were selected as controls. Superficial vessel density (SVD) and superficial perfusion density (SPD) in the macular and peripapillary regions were assessed by optical coherence tomography angiography (OCTA). Best-corrected visual acuity (BCVA) was assessed using LogMAR.
Results
Fifty eyes were administered SO tamponade, 54 SO tamponade(SOT) contralateral eyes, 29 PPV + C3F8 eyes, and 27 PPV + C3F8 contralateral eyes were selected. SVD and SPD in the macular region were lower in eyes administered SO tamponade compared with SOT contralateral eyes (P < 0.01). Except for the central area, SVD and SPD in the other areas of the peripapillary region were reduced after SO tamponade without SO removal (P < 0.01). No significant differences were found in SVD and SPD between PPV + C3F8 contralateral and PPV + C3F8 eyes. After SO removal, macular SVD and SPD showed significant improvements compared with preoperative values, but no improvements in SVD and SPD were observed in the peripapillary region. BCVA (LogMAR) decreased post-operation and was negatively correlated with macular SVD and SPD.
Conclusions
SVD and SPD are decreased during SO tamponade and increased in the macular region of eyes that underwent SO removal, suggesting a possible mechanism for reduced visual acuity during or after SO tamponade.
Trial registration
Registration date: 22/05/2019; Registration number, ChiCTR1900023322; Registration site, Chinese Clinical Trial Registry (ChiCTR).
... When the unavoidable chain of degeneration reaches to the INL, the RGC loss happens and it causes the poor results of therapies. Formation of subretinal vascular complexes is one the latest events occur during wide RP death [44]. Following PR degeneration, the retina shows the high level of hyperoxia which supresses the VEGF secretion [45]. ...
... Following PR degeneration, the retina shows the high level of hyperoxia which supresses the VEGF secretion [45]. Also, the breakdown of blood-retina barrier [44] and disorganization of RPE layer via new vasculture complex, leads to irreversible retinal diorders which affect the final results of therapies [46]. ...
Photoreceptors (PRs), as the most abundant and light-sensing cells of the neuroretina, are responsible for converting light into electrical signals that can be interpreted by the brain. PR degeneration, including morphological and functional impairment of these cells, causes significant diminution of the retina’s ability to detect light, with consequent loss of vision. Recent findings in ocular regenerative medicine have opened promising avenues to apply neuroprotective therapy, gene therapy, cell replacement therapy, and visual prostheses to the challenge of restoring vision. However, successful visual restoration in the clinical setting requires application of these therapeutic approaches at the appropriate stage of the retinal degeneration. In this review, firstly, we discuss the mechanisms of PR degeneration by focusing on the molecular mechanisms underlying cell death. Subsequently, innovations, recent developments, and promising treatments based on the stage of disorder progression are further explored. Then, the challenges to be addressed before implementation of these therapies in clinical practice are considered. Finally, potential solutions to overcome the current limitations of this growing research area are suggested. Overall, the majority of current treatment modalities are still at an early stage of development and require extensive additional studies, both pre-clinical and clinical, before full restoration of visual function in PR degeneration diseases can be realized.
Graphical Abstract
... Finally, sections were washed in PBS and mounted with a mounting media containing DAPI (4 ′ ,6-diamidino-2-phenylindole; Vectashield Mounting Medium con DAPI, Vector Atom, Alicante, España) to counterstain all retinal nuclei. Some additional sections of some animals were also processed for TdT-mediated dUTP nick-end labeling (TUNEL) to label apoptotic nuclei [50,60,61]. ...
... In each selected retinal section four photomicrographs were taken both in the dorsal and the ventral retina at distances representing 25, 50, 75 and 95% of the length between the optic disc and the retinal periphery. The number of nuclei rows in the outer nuclear layer (ONL) was quantified in three representative regions of each of these photomicrographs and averaged, obtaining a mean number or nuclei rows per picture, per retinal region analyzed and per animal [3,27,[49][50][51]60,61]. Therefore, a total of 24 microphotographs (8 photos x 3 sections) were analyzed per animal [27,50]. ...
... We also document that taurine treatment decreases the macroglial cell reaction in the RCS rat retina because in the taurine treated animals the Müller cells did not show GFAP immunoreactivity. Microglial cell activation, migration and proliferation [27,50,65], increased expression of GFAP by Müller cells [65,67,68] and hypertrophy of Müller cells [65,[67][68][69][70], are usually found in photoreceptor degenerative diseases and have been related to secondary retinal remodeling [1,2,5,65] and subsequent retinal ganglion cell death [2][3][4]53,60]. Taurine treatment has been previously documented to reduce the microglia-dependent inflammation in a mouse model of Parkinson's Disease [71] and to decrease the accumulation of GFAP in the brain in a rat model of traumatic brain injury [72]. ...
The aim of our work was to study whether taurine administration has neuroprotective effects in dystrophic Royal College of Surgeons (RCS) rats, suffering retinal degeneration secondary to impaired retinal pigment epithelium phagocytosis caused by a MERTK mutation. Dystrophic RCS-p + female rats (n = 36) were divided into a non-treated group (n = 16) and a treated group (n = 20) that received taurine (0.2 M) in drinking water from postnatal day (P)21 to P45, when they were processed. Retinal function was assessed with electroretinogram. Retinal morphology was assessed in cross-sections using immunohistochemical techniques to label photoreceptors, retinal microglial and macroglial cells, active zones of conventional and ribbon synaptic connections, and oxidative stress. Retinal pigment epithelium function was examined using intraocular fluorogold injections. Our results document that taurine treatment increases taurine plasma levels and photoreceptor survival in dystrophic rats. The number of photoreceptor nuclei rows at P45 was 3-5 and 6-11 in untreated and treated animals, respectively. Electroretinograms showed increases of 70% in the rod response, 400% in the a-wave amplitude, 30% in the b-wave amplitude and 75% in the photopic b-wave response in treated animals. Treated animals also showed decreased numbers of microglial cells in the outer retinal layers, decreased glial fibrillary acidic protein (GFAP) expression in Müller cells, decreased oxidative stress in the outer and inner nuclear layers and improved maintenance of synaptic connections. Treated animals showed increased FG phagocytosis in the retinal pigment epithelium cells. In conclusion, systemic taurine treatment decreases photoreceptor degeneration and increases electroretinographic responses in dystrophic RCS rats and these effects may be mediated through various neuroprotective mechanisms.
... Considering the absence of significant differences in OCTA-studied parameters in Macula-ON eyes between SO and gas groups, we could hypothesize a not primarily ischemic-pattern-retinal impairment for the explanation of the above-mentioned worst BCVA in SO filled eyes. Loss of retinal sensitivity might be led by toxic insult, phototoxicity and failure of potassium siphoning by Muller cells [39][40][41][42][43][44][45]. Furthermore, a longterm vitreous replacement by SO could lead to the impairment of normal ions exchanges between the retina and the vitreous, and this could explain the inverse relationship between the SCP VD and the duration of the OS tamponade [43]. ...
Background:
The aim of this study was to assess long-term macular vascular changes and their correlation with functional recovery in patients successfully treated for Macula-ON and Macula-OFF rhegmatogenous retinal detachment (RRD).
Methods:
This retrospective observational study included 82 eyes of 82 patients who received primary successful retinal detachment surgery, 33 Macula-ON and 49 Macula-OFF. Superficial and deep capillary plexuses (SCP and DCP) were evaluated by optical coherence tomography angiography (OCTA), and were correlated with visual acuity (VA), surgical technique and tamponade at 12 months after surgery. The fellow eyes were used as controls.
Results:
At 12-month follow-up, there was a significant decrease in the vessel density (VD) in the SCP in the operated eyes compared to control eyes (p < 0.05) in both the Macula-ON and Macula-OFF groups. Vessel length density (VLD) decrease in SCP was more extended in the Macula-OFF group. No difference in the DCP perfusion parameters was found, compared to controls. Subgroup analysis dependent on the type of surgery or tamponade showed no significant differences of VD and VLD. An inverse correlation was found between the SCP VD and the duration of silicone oil (SO) tamponade (p = 0.039). A significant correlation was observed between parafoveal SCP VD and final best corrected visual acuity (BCVA) (p = 0.028). The multivariate linear regression analysis showed that only the type of tamponade was significantly correlated with the final BCVA in the Macula-ON group (p = 0.004).
Conclusions:
Our study described long-term perfusion changes in RRD after surgery, with lower SCP VD and VLD in the operated eyes compared to the fellow ones, not influenced by type of surgery or tamponade. The choice of tamponade and SO removal timing may affect functional outcomes, especially in Macula-ON RRD. In conclusion, such functional and perfusion changes can be considered biomarkers that highlight the relevance of careful management of this sight-threatening disease.
... An intriguing aspect of the photoreceptor degenerative diseases is that they always trigger a progressive and extensive remodeling of the retina, which eventually leads in the death of the inner retinal neurons (Garcia-Ayuso et al. 2018a;Garcia-Ayuso et al. 2018b;Garcia-Ayuso et al. 2019a;Garcia-Ayuso et al. 2019b;Pfeiffer et al. 2020). It is believed that if a neuroprotective therapy such as photoreceptor replacement is applied early in the disease, this remodeling may be avoided before affecting the inner retina (Villegas-Perez et al. 1998;Marco-Gomariz et al. 2006;Garcia-Ayuso et al. 2010;Garcia-Ayuso et al. 2011;Garcia-Ayuso et al. 2018a;Garcia-Ayuso et al. 2018b;Garcia-Ayuso et al. 2019a;Garcia-Ayuso et al. 2019b;Pfeiffer et al. 2020). ...
Purpose:
To study and compare effects of syngeneic bone marrow mononuclear stem cells (BM-MNCs) transplants on inherited retinal degeneration in two animal models with different etiologies: the RCS and the P23H-1 rats. To compare the safety and efficacy of two methods of intraocular delivery: subretinal and/or intravitreal.
Methods:
A suspension of BM-MNCs was injected subretinally or intravitreally in the left eyes of P23H-1 and RCS rats at post-natal day (P) 21. At different survival intervals after the injection: 7, 15, 30 or 60 days, the retinas were cross-sectioned, and photoreceptor survival and glial cell responses were investigated using immunodetection of cones (anti-cone arrestin), synaptic connections (anti-bassoon), microglia (anti-Iba-1), astrocytes and Müller cells (anti-GFAP). Electroretinographic function was also assessed longitudinally.
Results:
Intravitreal injections (IVIs) or subretinal injections (SRIs) of BM-MNCs did not produce adverse effects. The transplanted cells survived for up to 15 days but did not penetrate the retina. Both IVIs and SRIs increased photoreceptor survival, decreased synaptic degeneration and glial fibrillary acidic protein (GFAP) expression in Müller cells but did not modify microglial cell activation and migration or the electroretinographic responses.
Conclusions:
Intravitreal and subretinal syngeneic BM-MNCs transplantation decreases photoreceptor degeneration and shows anti-gliotic effects on Müller cells but does not ameliorate retinal function. Moreover, syngeneic BM-MNCs transplants are more effective than the xenotransplants of these cells. BM-MNC transplantation has potential therapeutic effects that merit further investigation.
... Although some works have documented that taurine is a retinal neuroprotectant [11,36,37] necessary for retinal cell development [9,10] and survival [4][5][6], it remains to be shown whether decreased taurine plasma levels may trigger retinal degeneration, its pathways, and if it involves the retinal glial cells. In this work, we study in rats the macro and microglial cell changes in two of our experimental models of retinal degeneration: taurine depletion-induced [4,6] and light-induced [4,6,38], to investigate whether the noxious effects of taurine deficiency in the retina are exacerbated by light exposure. ...
... In this study and in previous studies [4,38,58,59] light exposure causes photoreceptor death that is manifested by significant thinning of the ONL in comparison with control and β-alanine non light-exposed animals. This death is exacerbated when β-alanine treatment is combined with light exposure, in accordance with our previous study [4]. ...
... This death is exacerbated when β-alanine treatment is combined with light exposure, in accordance with our previous study [4]. The experimental model of light-induced retinal degeneration used in this work causes rapid and progressive degeneration of both rods and cones, disruption of the photoreceptor mosaic and long-term alterations in all retinal layers, namely retinal remodeling, leading to retinal ganglion cell loss [27,38,43,60,61]. Some authors have proposed that taurine depletion-induced retinal degeneration is light dependent [3,5,16,[62][63][64], and more recently we have confirmed that taurine depletion increases photoreceptor sensitivity to light [4]. ...
We investigate glial cell activation and oxidative stress induced by taurine deficiency secondary to β-alanine administration and light exposure. Two months old Sprague-Dawley rats were divided into a control group and three experimental groups that were treated with 3% β-alanine in drinking water (taurine depleted) for two months, light exposed or both. Retinal and external thickness were measured in vivo at baseline and pre-processing with Spectral-Domain Optical Coherence Tomography (SD-OCT). Retinal cryostat cross sections were immunodetected with antibodies against various antigens to investigate microglial and macroglial cell reaction, photoreceptor outer segments, synaptic connections and oxidative stress. Taurine depletion caused a decrease in retinal thickness, shortening of photoreceptor outer segments, microglial cell activation, oxidative stress in the outer and inner nuclear layers and the ganglion cell layer and synaptic loss. These events were also observed in light exposed animals, which in addition showed photoreceptor death and macroglial cell reactivity. Light exposure under taurine depletion further increased glial cell reaction and oxidative stress. Finally, the retinal pigment epithelial cells were Fluorogold labeled and whole mounted, and we document that taurine depletion impairs their phagocytic capacity. We conclude that taurine depletion causes cell damage to various retinal layers including retinal pigment epithelial cells, photoreceptors and retinal ganglion cells, and increases the susceptibility of the photoreceptor outer segments to light damage. Thus, beta-alanine supplements should be used with caution.
... Since then, the interest of researchers on retinal phototoxicity has been increased and numerous phototoxicity models have been developed. These models can be classified according to: (i) in vitro or in vivo studies [21][22][23][24][25][26][27][28][29][30][31]; (ii) wavelength of light: although white light have been the most studied by researchers [23,26,[32][33][34][35], other light spectra such as blue light (400-470 nm) [22][23][24]26,[36][37][38][39][40][41][42][43][44] or green light (507-535 nm) [22,23,31,45] have also been studied; (iii) light source: fluorescent sources [33][34][35]41,[46][47][48] or LED sources [22,23,26,32,[36][37][38][39]42,43,49,50]; (iv) intensity and duration of photo-exposure: focal models require short exposure times [37][38][39][40]44,50] while the diffuse models require longer exposure times [22,23,26,33,34,36,[41][42][43]46,47]. ...
... Since then, the interest of researchers on retinal phototoxicity has been increased and numerous phototoxicity models have been developed. These models can be classified according to: (i) in vitro or in vivo studies [21][22][23][24][25][26][27][28][29][30][31]; (ii) wavelength of light: although white light have been the most studied by researchers [23,26,[32][33][34][35], other light spectra such as blue light (400-470 nm) [22][23][24]26,[36][37][38][39][40][41][42][43][44] or green light (507-535 nm) [22,23,31,45] have also been studied; (iii) light source: fluorescent sources [33][34][35]41,[46][47][48] or LED sources [22,23,26,32,[36][37][38][39]42,43,49,50]; (iv) intensity and duration of photo-exposure: focal models require short exposure times [37][38][39][40]44,50] while the diffuse models require longer exposure times [22,23,26,33,34,36,[41][42][43]46,47]. ...
... Since then, the interest of researchers on retinal phototoxicity has been increased and numerous phototoxicity models have been developed. These models can be classified according to: (i) in vitro or in vivo studies [21][22][23][24][25][26][27][28][29][30][31]; (ii) wavelength of light: although white light have been the most studied by researchers [23,26,[32][33][34][35], other light spectra such as blue light (400-470 nm) [22][23][24]26,[36][37][38][39][40][41][42][43][44] or green light (507-535 nm) [22,23,31,45] have also been studied; (iii) light source: fluorescent sources [33][34][35]41,[46][47][48] or LED sources [22,23,26,32,[36][37][38][39]42,43,49,50]; (iv) intensity and duration of photo-exposure: focal models require short exposure times [37][38][39][40]44,50] while the diffuse models require longer exposure times [22,23,26,33,34,36,[41][42][43]46,47]. ...
Phototoxicity animal models have been largely studied due to their degenerative com-
munalities with human pathologies, e.g., age-related macular degeneration (AMD). Studies have
documented not only the effects of white light exposure, but also other wavelengths using LEDs,
such as blue or green light. Recently, a blue LED-induced phototoxicity (LIP) model has been devel-
oped that causes focal damage in the outer layers of the superior-temporal region of the retina in
rodents. In vivo studies described a progressive reduction in retinal thickness that affected the most
extensively the photoreceptor layer. Functionally, a transient reduction in a- and b-wave amplitude
of the ERG response was observed. Ex vivo studies showed a progressive reduction of cones and an
involvement of retinal pigment epithelium cells in the area of the lesion and, in parallel, an activation
of microglial cells that perfectly circumscribe the damage in the outer retinal layer. The use of
neuroprotective strategies such as intravitreal administration of trophic factors, e.g., basic fibroblast
growth factor (bFGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF)
or pigment epithelium-derived factor (PEDF) and topical administration of the selective alpha-2
agonist (Brimonidine) have demonstrated to increase the survival of the cone population after LIP.
... However, it has been documented that there are other environmental factors that may favour the onset of this disease, such as exposure to light [5][6][7]. Because of this, many animal studies have focused on the study of the degeneration process of photoreceptors, both in inherited models [8][9][10][11][12][13] and in models of induced phototoxicity [5,[14][15][16][17][18]. In the development of phototoxicity induction models, many recent studies have used light-emitting diode (LED) sources that show a deleterious effect of the light with an involvement of the retina, more aggressive in the outer region affecting photoreceptors and retinal pigment epithelium (RPE) cells [15,[18][19][20][21][22][23][24]. ...
Background:
In adult rats we study the short- and long-term effects of focal blue light-emitting diode (LED)-induced phototoxicity (LIP) on retinal thickness and Iba-1+ activation.
Methods:
The left eyes of previously dark-adapted Sprague Dawley (SD) rats were photoexposed to a blue LED (20 s, 200 lux). In vivo longitudinal monitoring of retinal thickness, fundus images, and optical retinal sections was performed from 1 to 30 days (d) after LIP with SD-OCT. Ex vivo, we analysed the population of S-cone and Iba-1+ cells within a predetermined fixed-size circular area (PCA) centred on the lesion.
Results:
LIP resulted in a circular focal lesion readily identifiable in vivo by fundus examination, which showed within the PCAs a progressive thinning of the outer retinal layer, and a diminution of the S-cone population to 19% by 30 d. In parallel to S-cone loss, activated Iba-1+ cells delineated the lesioned area and acquired an ameboid morphology with peak expression at 3 d after LIP. Iba-1+ cells adopted a more relaxed-branched morphology at 7 d and by 14-30 d their morphology was fully branched.
Conclusion:
LIP caused a progressive reduction of the outer retina with loss of S cones and a parallel dynamic activation of microglial cells in the lesioned area.
