Marta Agudo‐Barriuso

Instituto Murciano de Investigación Biosanitaria

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Manuel Vidal‐Sanz

Universidad de Murcia

147

Francisco M. Nadal‐Nicolás

National Institutes of Health

María Paz Villegas‐Pérez

Universidad de Murcia

Caridad Galindo‐Romero

Universidad de Murcia

Manuel Jiménez-López

Instituto Murciano de Investigación Biosanitaria

Diego García‐Ayuso

Universidad de Murcia

Francisco J. Valiente‐Soriano

Universidad de Murcia

Manuel Salinas‐Navarro

Universidad de Murcia

Johnny Di Pierdomenico

Universidad de Murcia

Paloma Sobrado‐Calvo

Universidad de Murcia

Cooperative Institutions

Universidad de Murcia

111

Instituto Murciano de Investigación Biosanitaria

Instituto de Salud Carlos III

Consejo Superior de Investigaciones Científicas

Universidad Autónoma de Madrid

Inserm

Institut de la Vision

Hospital Universitario Virgen de la Arrixaca

Centro de Biología Molecular Severo Ochoa

Centre National de la Recherche Scientifique

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Brimonidine reduces the increased expression of nestin in rat Müller cells after transient retinal ischemia

Ulrika Lönngren Inmaculada Sellés-Navarro Marta Agudo‐Barriuso Ulla Näpänkangas Manuel Vidal‐Sanz

Retinal ganglion cells play a crucial role in the relay of visual signals from the eye to the brain. This cell type is affected and eventually lost in the eye disease glaucoma, resulting in progressive and irreversible loss of vision. Studies of the molecular mechanisms leading to retinal ganglion cell death are important for the understanding of the disease and for designing future treatments. This thesis addresses and studies these molecular mechanisms, including alterations in gene expression after experimental retinal injuries. The effects of a neuroprotective drug, brimonidine, after transient retinal ischemia were also studied in order to help explain the mechanisms behind the protective properties of this drug.Several methods, including quantitative reverse transcriptase PCR, micro-arrays, western blot and immunohistochemistry, were used. The results showed that transient retinal ischemia triggers cell division in Muller cells and alters the gene expression of growth factors, their receptors, and intermediate filaments in the retina. Several genes related to the apoptosis process were less affected. Pre-treatment with brimonidine increased the levels of certain growth factors (BDNF, NT3, CNTF, FGF9) compared with vehicle. Brimonidine also had marked effects on genes related to progenitor cells, among them the recognized neural stem cell marker nestin. The increase in levels of nestin after ischemia was countered by brimonidine treatment. Moreover, retinal ganglion cell death following either optic nerve transection or optic nerve crush appears to involve the extrinsic apoptotic pathway although the gene expression response appears to differ between these injuries.The results obtained in this work contribute to an increased understanding of retinal injuries and highlight the importance of Muller cells in the endogenous defense against retinal injuries.

Brimonidine

Nestin

PAX6

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Effect of olfactory ensheathing glia clone TEG3 on neuroprotection, microglial activation and gene expression profile of allotransplanted retina with and without immunosuppression

Acta Ophthalmologica (2022)

María Norte Muñoz María Portela‐Lomba Paloma Sobrado‐Calvo Johnny Di Pierdomenico Manuel Vidal‐Sanz

Abstract Purpose: Olfactory ensheathing glia (OEG) is a macroglia from the embryonic ectoderm, with unique functions in guiding sensory axons from the olfactory mucosa (PNS) to the olfactory bulb (CNS). These properties, together with their high secretion of trophic factors, have made its use a field of study in axonal regeneration. However, their in vivo administration in the retina had never been tested, so we set out to evaluate their actions in the retina without injury and after an optic nerve crush (ONC) model. In addition, to simulate the clinical conditions of an allogeneic cell transplant, we evaluated how their properties were altered when combined with immunosuppressive treatment. Methods: Wistar TEG3‐GFP + cells were administered into the vitreous of SD female rats. Experimental groups: transplantation in intact retinas, in retinas just after ONC, and both with systemic immunosuppression. In some animals of each group, the retina was dissected for anatomical analysis and the total number of retinal ganglion cells (RGCs) was counted and the morphological activation of microglia was studied. The retinas of the remaining animals were dissected fresh for the study of gene expression by real‐time quantitative PCR. Animals injected with vehicles after ONC and intact animals without injury were used as controls. n = 3–8 animals/group/analysis. Results: TEG3 neuroprotected RGCs after ONC at 7 days (18% more survival compared to vehicle group p < 0.05) but caused a large activation of microglia cells coupled with a 33% ( p < 0.01) reduction of RGCs 21 after transplantation in intact retinas. Immunosuppression had no effect on neuroprotective properties but did recover some of the death observed at 21 days in intact retinas (up to a 17%, p < 0,05). Immunosuppression reduced the expression of pro‐inflammatory molecules ( Tnf , Il6 ), macrogliosis markers ( Gfap ) and macrophage markers ( Ptprc ) in favour of anti‐inflammatory ones ( Il10 ). However, markers of pyroptotic cell death ( Casp4 , Gsdmd ) did not change after treatment, which would explain the elevated microglial activation and death observed at 21 days in intact and grafted retinas. Conclusions: TEG3 has a dual effect neurotoxic and neuroprotective in retina.

Olfactory ensheathing glia

Muller glia

10.1111/j.1755-3768.2022.0787

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Time course profiling of the retinal transcriptome after optic nerve transection and optic nerve crush.

PubMed (2008)

Marta Agudo‐Barriuso Maria Cruz Pérez-Marín Ulrika Lönngren P. Sobrado Ana Conesa

A time-course analysis of gene regulation in the adult rat retina after intraorbital nerve crush (IONC) and intraorbital nerve transection (IONT).RNA was extracted from adult rat retinas undergoing either IONT or IONC at increasing times post-lesion. Affymetrix RAE230.2 arrays were hybridized and analyzed. Statistically regulated genes were annotated and functionally clustered. Arrays were validated by means of quantative reverse transcription polymerase chain reaction (qRT-PCR) on ten regulated genes at two times post-lesion. Western blotting and immunohistofluorescence for four pro-apoptotic proteins were performed on naïve and injured retinas. Finally, custom signaling maps for IONT- and IONC-induced death response were generated (MetaCore, Genego Inc.).Here we show that over time, 3,219 sequences were regulated after IONT and 1,996 after IONC. Out of the total of regulated sequences, 1,078 were commonly regulated by both injuries. Interestingly, while IONT mainly triggers a gene upregulation-sustained over time, IONC causes a transitory downregulation. Functional clustering identified the regulation of high interest biologic processes, most importantly cell death wherein apoptosis was the most significant cluster. Ten death-related genes upregulated by both injuries were used for array validation by means of qRT-PCR. In addition, western blotting and immunohistofluorescence of total and active Caspase 3 (Casp3), tumor necrosis factor receptor type 1 associated death domain (TRADD), tumor necrosis factor receptor superfamily member 1a (TNFR1a), and c-fos were performed to confirm their protein regulation and expression pattern in naïve and injured retinas. These analyses demonstrated that for these genes, protein regulation followed transcriptional regulation and that these pro-apoptotic proteins were expressed by retinal ganglion cells (RGCs). MetaCore-based death-signaling maps show that several apoptotic cascades were regulated in the retina following optic nerve injury and highlight the similarities and differences between IONT and IONC in cell death profiling.This comprehensive time course retinal transcriptome study comparing IONT and IONC lesions provides a unique valuable tool to understand the molecular mechanisms underlying optic nerve injury and to design neuroprotective protocols.

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Study of the functional integrity of the retinal pigment epithelium with a new technique in two models of inherited retinal degeneration

Acta Ophthalmologica (2019)

Johnny Di Pierdomenico Francisco Javier Valiente Soriano Manuel Salinas Navarro Diego García‐Ayuso María Paz Villegas‐Pérez

Abstract Introduction Retinal pigment epithelium (RPE) is a cell layer located between the neurosensory retina and the choroid. RPE has many functions that are essential for photoreceptor nutrition and renewal, among others. To understand the pathogenesis of retinal degenerations, it is crucial to study the integrity, morphology and functionality of this layer. Material and methods Dystrophic young and old adult female albino P23H‐1 (rhodopsin mutation) and Royal College of Surgeon, (RCS, RPE mutation that impairs phagocytosis), rats were used in this experiment. Control strains were Sprague‐Dawley (SD) and Pievald Virol Glaxo (PVG). To label the RPE, 1.5 µl of 3% Fluorogold (FG) diluted in saline was administered intravitreally under general anaesthesia. RPE in‐vivo analysis were performed with SD‐OCT and by eye fundus observation; for ex‐vivo analysis flat mounted RPE and cryostat cross‐sections were used. Results In‐vivo analysis of the dystrophic strains showed an overexpression of lipofuscin in the RPE and a reduction of the retinal thickness, both pathological conditions increased with time. Ex‐vivo analysis in cross sections revealed that in control SD and PVG rats, RPE was labelled with FG showing its typical cubic morphology. The retinal structure and RPE morphology however, was altered in the dystrophic strains. In flat mounts we observed that FG accumulates inside the somas of RPE cells in SD, PVG and young P23H‐1 rats, indicating that the RPE has a correct function. However, in old P23H‐1 rats, FG was found inside and outside the RPE somas, which in addition were bigger and unstructured. When analysing RCS rats, we observed that FG accumulated outside the RPE somas, indicative of the phagocytosis malfunction that characterises this strain. Conclusions Intraocular injection of FG is a reliable technique to label functional RPE. In both models of inhered retinal degeneration RPE functional integrity was affected by the evolution of degeneration.

Ex vivo

Fundus (uterus)

Lipofuscin

Choroid

Electroretinography

10.1111/j.1755-3768.2019.5199

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Perinatal derivatives application: Identifying possibilities for clinical use

Frontiers in Bioengineering and Biotechnology (2022)

Florelle Gindraux Nicola Hofmann Marta Agudo‐Barriuso Mariastefania Antica Pedro Silva Couto

Perinatal derivatives are drawing growing interest among the scientific community as an unrestricted source of multipotent stromal cells, stem cells, cellular soluble mediators, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options by means of developing regenerative approaches. In this paper, to generate a complete view of the state of the art, a comprehensive 10-years compilation of clinical-trial data with the common denominator of PnD usage has been discussed, including commercialized products. A set of criteria was delineated to challenge the 10-years compilation of clinical trials data. We focused our attention on several aspects including, but not limited to, treated disorders, minimal or substantial manipulation, route of administration, dosage, and frequency of application. Interestingly, a clear correlation of PnD products was observed within conditions, way of administration or dosage, suggesting there is a consolidated clinical practice approach for the use of PnD in medicine. No regulatory aspects could be read from the database since this information is not mandatory for registration. The database will be publicly available for consultation. In summary, the main aims of this position paper are to show possibilities for clinical application of PnD and propose an approach for clinical trial preparation and registration in a uniform and standardized way. For this purpose, a questionnaire was created compiling different sections that are relevant when starting a new clinical trial using PnD. More importantly, we want to bring the attention of the medical community to the perinatal products as a consolidated and efficient alternative for their use as a new standard of care in the clinical practice.

Clinical Practice

Regenerative Medicine

10.3389/fbioe.2022.977590

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Retinal Ganglion Cell Axonal Constriction and Death in the P23H-1 Rat Retina

Investigative Ophthalmology & Visual Science (2010)

Diego García‐Ayuso M. Salinas–Navarro Marta Agudo‐Barriuso Leticia Nieto-López Nicolás Cuenca

Constriction

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Course of retinal ganglion cell loss and microglial activation in two models of neuronal degeneration

Acta Ophthalmologica (2022)

María Josefa González Riquelme Fernando Lucas‐Ruiz Raquel Boia Ana Raquel Santiago Manuel Vidal‐Sanz

Abstract Purpose Organotypic retinal cultures (COR) are inherently a model of retinal axotomy and detachment. In vivo, optic nerve axotomy causes degeneration of retinal ganglion cells (RGCs). Our objective is to evaluate and compare the time course of RGC death and the activation of microglial cells (MCs) in vivo and in vitro . Methods C57/Bl6 mice were used. For the in vitro model, retinas were dissected and cultured in supplemented medium, and axotomy in vivo was done to the left optic nerve. In both models, retinas were analyzed from 24 hours to 9 days. RGCs were immunodetected with Brn3a, MCs with Iba1 and the density in the medial retinal area was quantified for both populations. Results The loss of RGCs was similar in vivo and in vitro during the first days, but from 5 days onwards RGC loss is quicker and more abrupt in vitro than in vivo . MC morphology differs between both models and their density is smaller in vitro than in vivo at all time points. Conclusions RGCs loss in vitro and in vivo follows the same kinetics at early time points. Morphologically, MCs seem to be differently activated in both models, and because their density is lower in vitro than in vivo , it is possible that in vivo either MCs or circulating macrophages invade the retina to cope with RGC degeneration.

Axotomy

10.1111/j.1755-3768.2022.211

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A dicentric chromosome of Drosophila melanogaster showing alternate centromere inactivation

Chromosoma (2000)

Marta Agudo‐Barriuso Jos x E P. Abad Isabel Molina Ana Losada Pedro Ripóll

Dicentric chromosome

10.1007/s004120050427

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Citations (41)

The senescent vision: dysfunction or neuronal loss?

Aging (2018)

Francisco M. Nadal‐Nicolás Manuel Vidal‐Sanz Marta Agudo‐Barriuso

10.18632/aging.101734

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Effect of the transplantation type on the neuroprotective properties of mesenchymal stromal cells

Acta Ophthalmologica (2024)

María Norte‐Muñoz David García‐Bernal Alejandro Gallego‐Ortega Fernando Lucas‐Ruiz Manuel Vidal‐Sanz

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.

Immunosuppression

10.1111/aos.16387

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