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Age‐related vision loss caused by retinal neurodegenerative pathologies is becoming more prevalent in our ageing society. To understand the physiological and molecular impact of ageing on retinal homeostasis, we used the short‐lived African turquoise killifish, a model known to naturally develop central nervous system (CNS) ageing hallmarks and vision loss. Bulk and single‐cell RNA‐sequencing (scRNAseq) of three age groups (6‐, 12‐, and 18‐week‐old) identified transcriptional ageing fingerprints in the killifish retina, unveiling pathways also identified in the aged brain, including oxidative stress, gliosis, and inflammageing. These findings were comparable to observations in the ageing mouse retina. Additionally, transcriptional changes in genes related to retinal diseases, such as glaucoma and age‐related macular degeneration, were observed. The cellular heterogeneity in the killifish retina was characterized, confirming the presence of all typical vertebrate retinal cell types. Data integration from age‐matched samples between the bulk and scRNAseq experiments revealed a loss of cellular specificity in gene expression upon ageing, suggesting potential disruption in transcriptional homeostasis. Differential expression analysis within the identified cell types highlighted the role of glial/immune cells as important stress regulators during ageing. Our work emphasizes the value of the fast‐ageing killifish in elucidating molecular signatures in age‐associated retinal disease and vision decline. This study contributes to the understanding of how age‐related changes in molecular pathways may impact CNS health, providing insights that may inform future therapeutic strategies for age‐related pathologies. [ABSTRACT FROM AUTHOR]

As the mammalian central nervous system matures, its regenerative ability decreases, leading to incomplete or non‐recovery from the neurodegenerative diseases and central nervous system insults that we are increasingly facing in our aging world population. Current neuroregenerative research is largely directed toward identifying the molecular and cellular players that underlie central nervous system repair, yet it repeatedly ignores the aging context in which many of these diseases appear. Using an optic nerve crush model in a novel biogerontology model, that is, the short‐living African turquoise killifish, the impact of aging on injury‐induced optic nerve repair was investigated. This work reveals an age‐related decline in axonal regeneration in female killifish, with different phases of the repair process being affected depending on the age. Interestingly, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of this impairment. Overall, we introduce the killifish visual system and its age‐dependent regenerative ability as a model to identify new targets for neurorepair in non‐regenerating individuals, thereby also considering the effects of aging on neurorepair. [ABSTRACT FROM AUTHOR]

The aging central nervous system (CNS) of mammals displays progressive limited regenerative abilities. Recovery after loss of neurons is extremely restricted in the aged brain. Many research models fall short in recapitulating mammalian aging hallmarks or have an impractically long lifespan. We established a traumatic brain injury model in the African turquoise killifish (Nothobranchius furzeri), a regeneration‐competent vertebrate that evolved to naturally age extremely fast. Stab‐wound injury of the aged killifish dorsal telencephalon unveils an impaired and incomplete regeneration response when compared to young individuals. In the young adult killifish, brain regeneration is mainly supported by atypical non‐glial progenitors, yet their proliferation capacity clearly declines with age. We identified a high inflammatory response and glial scarring to also underlie the hampered generation of new neurons in aged fish. These primary results will pave the way to unravel the factor age in relation to neurorepair, and to improve therapeutic strategies to restore the injured and/or diseased aged mammalian CNS. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a neurodegenerative disorder that is the leading cause of dementia, affecting more than 50 million people worldwide. In the search for new biomarkers, increasing attention has been dedicated to the retina. As part of the central nervous system, the retina manifests many of the characteristic pathological processes that occur in the AD brain. Moreover, it can be imaged at low‐cost and non‐invasively at high resolution, and therefore it may be used for AD diagnosis and monitoring. In this context, emerging evidence suggests the potential of in vivo hyperspectral retinal imaging (HSRI) as a potential biomarker for brain amyloid‐β accumulation. Therefore, this project aims at studying HSRI as a novel biomarker that could lead to inexpensive population screening, thereby removing one of the principal bottlenecks to therapeutic advances in AD. Method: In this study, we seek to define the molecular basis, sensitivity, and specificity of the HSRI signal of AD, and whether it can distinguish AD from other dementias in a translational pre‐clinical and clinical research project. We perform HSRI of synthetic protein aggregates, and different cell and mouse models of neurodegenerative proteinopathies, and correlate these data with molecular biology assays, to study the molecular basis and pathological correlates of HSRI signals. In a parallel clinical study, we assess the correlation between amyloid status and HSRI and evaluate whether the diagnostic power of HSRI can be increased via a multimodal imaging approach. Result: Our preliminary results demonstrate that HSRI can be used to quantify retinal amyloid in AD animal models and post‐mortem tissues as well as discriminate between AD patients and controls, with improvement in classification accuracy by including optical coherence tomography (OCT) data. Conclusion: This research study covers out‐of‐the‐box thinking to transform the detection of AD. It collects evidence of the specificity and molecular basis of HSRI which is essential for its rational clinical use as an AD imaging biomarker. [ABSTRACT FROM AUTHOR]

Background: Both epidemiological and animal studies have previously indicated a link between in utero radiation exposure and birth defects such as microphthalmos, anophthalmos, and exencephaly. However, detailed knowledge on embryonic radiosensitivity during different stages of neurulation is limited, especially in terms of neural tube defect and eye defect development. Methods: To assess the most radiosensitive stage during neurulation, pregnant C57BL6/J mice were X-irradiated (0.5 Gy or 1.0 Gy) at embryonic days (E)7, E7.5, E8, E8.5, or E9. Next, the fetuses were scored macroscopically for various defects and prenatal resorptions/deaths were counted. In addition, cranial skeletal development was ascertained using the alcian-alizarin method. Furthermore, postnatal/young adult survival was followed until 5 weeks (W5) of age, after X-irradiation at E7.5 (0.1 Gy, 0.5 Gy, or 1.0 Gy). In addition, body and brain weights were registered at adult age (W10) following X-ray exposure at E7.5 (0.1 Gy, 0.5 Gy). Results: Several malformations, including microphthalmos and exencephaly, were most evident after irradiation at E7.5, with significance starting respectively at 0.5 Gy and 1.0 Gy. Prenatal mortality and weight were significantly affected in all irradiated groups. Long-term follow-up of E7.5 irradiated animals revealed a reduction in survival at 5 weeks of age after high dose exposure (1.0 Gy), while lower doses (0.5 Gy, 0.1 Gy) did not affect brain and body weight at postnatal week 10. Conclusions: With this study, we gained more insight in radiosensitivity throughout neurulation, and offered a better defined model to further study radiation-induced malformations and the underlying mechanisms. [ABSTRACT FROM AUTHOR]

The rise in life expectancy in our modern societies concurs with an increasing prevalence of age‐associated neurodegenerative disorders and central nervous system (CNS) trauma. Despite many research attempts trying to unravel aging processes and their role in functional decline, the mechanisms underlying healthy CNS aging remain elusive. Moreover, the reparative approaches proposed to combat loss of neurons due to damage or (age‐associated) disease are failing. One of the reasons might be that the currently used animal models often lack the capability to properly recapitulate the aged environment in which these pathologies manifest and the repair processes need to occur. We introduce the African turquoise killifish as an opportune model to study CNS aging as well as neuroreparative strategies. Indeed, while sharing adult neuroregenerative potential with other teleost fish like zebrafish, the short‐lived killifish displays many of the human aging hallmarks, making it a promising biogerontology model. As vision decline manifests during human aging and in many neurodegenerative diseases, we performed a comprehensive characterization of the aged killifish visual system, comprising the retina, optic projections and optic tectum. Immunohistochemical, biochemical and molecular analyses revealed the presence of many aging traits in this system, including oxidative stress, genomic damage, cellular senescence, altered cellular communication, reduced neurogenic potential and even neurodegeneration. Specifically, microglia changed to a pro‐inflammatory secretion profile upon aging and macroglia became gliotic in the aging killifish visual system. Altogether, these age‐related changes led to a diminished visual performance in old killifish. Using an optic nerve injury model, we further disclosed an age‐related decline in functional circuit restoration, with different phases of the repair process being affected depending on the age. While young adult killifish were able to functionally recover after injury, old fish did not regain vision at all. Here we observed for the first time in a regenerative teleost fish model, a glial scar that formed a mechanical barrier physically preventing axonal regrowth. Moreover, in the optic tectum the inflammatory response shifted from acute to chronic upon aging. Macroglia, which showed a transient gliotic response after injury in young adult fish, displayed a permanent response in old animals. Overall, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment, orchestrated by activated micro‐ and macroglia, were found to underlie the declined repair potential in aged killifish. To decode the cellular and molecular framework that defines visual system aging and the failed regenerative response in old fish, we are currently performing single‐cell RNA sequencing of the young adult and aged killifish retina. We envision our bioinformatic approaches to result in innovative druggable targets for future development of rejuvenative/curative therapies in the aged mammalian retina. In summary, our study highlights the importance of a neuron–glia crosstalk in health, disease and repair. It puts forward the strengths of the killifish as a vertebrate model with mammalian‐like characteristics upon aging, that offers unique opportunities to identify rejuvenating and neuroreparative strategies ensuring healthy aging. [ABSTRACT FROM AUTHOR]

ABSTRACT Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Purpose To determine the optimum administration route of bevacizumab after glaucoma filtering surgery ( GFS) and to investigate whether a reduced dose of mitomycin-C ( MMC) in combination with bevacizumab could improve surgical outcome with a reduced incidence of side-effects. Methods Plasma levels of bevacizumab were determined via ELISA after intracameral ( IC), subconjunctival ( SC) and intravitreal ( IV) injections in mice, subjected to a mouse model of GFS. Application of MMC was compared to bevacizumab ( SC, 25 μg) and to the combined use of both adjuvants. Surgical sponges soaked in MMC 0.02% or 0.01% were exposed to the sclera for 1 or 2 min. Treatment outcome was studied by bleb investigation. Results The three administration routes of bevacizumab equally improved surgical outcome. The VEGF antibody was detected at relatively high levels in plasma shortly after IV injection, whereas it was minimally absorbed after IC and SC injections. Both bevacizumab ( SC) and MMC 0.02% (2 min) similarly increased bleb area. As compared to MMC, the combined injection with bevacizumab induced an additional effect on surgical outcome. Exposure of MMC 0.02% for 1 or 2 min together with bevacizumab equally improved surgical outcome, but 2 min application induced corneal toxicity. The combined use of bevacizumab and 1-min MMC 0.01% also improved surgical outcome compared to monotherapy, although to a lesser extent than the combination with 1-min MMC 0.02%. Conclusions Adjunctive bevacizumab not only enhances the beneficial effect of MMC on surgical outcome, but also allows reducing the administration time of MMC 0.02%, thereby eliminating its toxic effects on the cornea. [ABSTRACT FROM AUTHOR]

Restoration of correct neural activity following central nervous system ( CNS) damage requires the replacement of degenerated axons with newly outgrowing, functional axons. Unfortunately, spontaneous regeneration is largely lacking in the adult mammalian CNS. In order to establish successful regenerative therapies, an improved understanding of axonal outgrowth and the various molecules influencing it, is highly needed. Matrix metalloproteinases ( MMPs) constitute a family of zinc-dependent proteases that were sporadically reported to influence axon outgrowth. Using an ex vivo retinal explant model, we were able to show that broad-spectrum MMP inhibition reduces axon outgrowth of mouse retinal ganglion cells ( RGCs), implicating MMPs as beneficial factors in axonal regeneration. Additional studies, using more specific MMP inhibitors and MMP-deficient mice, disclosed that both MMP-2 and MT1- MMP, but not MMP-9, are involved in this process. Furthermore, administration of a novel antibody to MT1- MMP that selectively blocks pro- MMP-2 activation revealed a functional co-involvement of these proteinases in determining RGC axon outgrowth. Subsequent immunostainings showed expression of both MMP-2 and MT1- MMP in RGC axons and glial cells. Finally, results from combined inhibition of MMP-2 and β1-integrin were suggestive for a functional interaction between these molecules. Overall, our data indicate MMP-2 and MT1- MMP as promising axonal outgrowth-promoting molecules. [ABSTRACT FROM AUTHOR]

Excessive post-operative wound healing with subsequent scarring frequently leads to surgical failure of glaucoma filtration surgery (trabeculectomy). We investigated the hypothesis that placental growth factor (Pl GF) plays a role in post-operative scar formation, and that it therefore may be a target for improvement of filtration surgery outcome. ELISA experiments showed that Pl GF levels were significantly increased in aqueous humour of glaucoma patients and after VEGF treatment, which may indicate an important contribution of this growth factor to wound healing after trabeculectomy. Using a mouse model of glaucoma filtration surgery, we were able to show that intracameral injection of a previously characterized anti-Pl GF antibody (ThromboGenics NV) significantly improved surgical outcome by increasing bleb survival and bleb area. This was associated with a significant reduction in post-operative proliferation, inflammation and angiogenesis during the first post-operative days after surgery, and with a decrease in collagen deposition at later stages. Furthermore, inhibition of Pl GF seemed to be more effective than anti- VEGF-R2 treatment in improving surgical outcome, possibly via its additional effect on inflammation. These results render Pl GF an appealing target for ocular wound healing and point to potential therapeutic benefits of Pl GF inhibition for the prevention of surgical failure. [ABSTRACT FROM AUTHOR]

Purpose: Previous research in the AppNL‐G‐F mouse has shown that hyperspectral retinal imaging (HSRI) can be used to quantify retinal amyloid burden in the preclinical stages of Alzheimer's disease (AD) [1]. This underscores its potential as an imaging biomarker for AD diagnosis and monitoring. One prerequisite for the rational implementation of HSRI as a biomarker, however, is a better understanding of the pathological correlate of the HSRI signature. In this follow‐up study, we explored HSRI signatures in different proteinopathies and identified the pathological features underlying the observed HSRI results. Methods: Retinal tissues were collected from mouse models with amyloid, tau and alpha‐synuclein overexpression/aggregation for ex vivo HSRI (Snapscan, Imec) [1]. HSRI was complemented with optical coherence tomography and electroretinograms (prior to HSRI) and immunohistochemistry and molecular studies of protein aggregation (after HSRI). Results: While all protein aggregates led to HSRI changes in the 450–600 nm range, distinct signatures were observed for amyloid, tau and alpha‐synuclein. Furthermore, the observed HSRI changes correlated with levels of the protein oligomerization and aggregation. Diverging patterns of retinal dysfunction/degeneration were observed in the different mouse models, illustrating the varied impacts of these protein aggregates on retinal structure and function. Conclusions: HSRI may be used to quantify retinal amyloid, tau and alpha‐synuclein, underscoring its potential as a biomarker for diagnosis and disease monitoring. Moreover, our data suggest that amyloid, tau and alpha‐synuclein accumulation lead to distinct HSRI signatures, thus adding further evidence that HSRI may have utility in the diagnosis and stratification of proteinopathies associated with the most common forms of neurodegenerative diseases. Bibliograph: Vandenabeele et al. (2021) Acta Neuropathol Commun 9(1):6. [ABSTRACT FROM AUTHOR]

The molecular chaperone αB-crystallin has emerged as a target for cancer therapy due to its expression in human tumors and its role in regulating tumor angiogenesis, αB-crystallin also reduces neuroinflammation, but its role in other inflammatory conditions has not been investigated. Here, we examined whether αB-crystallin regulates inflammation associated with tumors and ischemia. We found that CD45+ leukocyte infiltration is 3-fold increased in tumors and ischemic myocardium in αB-crystallin-deficient mice. Notably, αB-crystallin is prominently expressed in CD11b+ Gr-1+ immature myeloid cells (IMCs), known as regulators of angiogenesis and immune responses, while lymphocytes and mature granulocytes show low αB-crystallin expression, αB-Crystallin deficiency results in a 3-fold higher accumulation of CD11b+ Gr-1+ IMCs in tumors and a significant rise in CD11b+ Gr-1+ IMCs in spleen and bone marrow. Similarly, we noted a 2-fold increase in CD11b+ Gr-1+ IMCs in chronically inflamed livers in αB-crystallin-deficient mice. The effect of αB-crystallin on IMC accumulation is limited to pathological conditions, as CD11b+ Gr-1+ IMCs are not elevated in naive mice. Through ex vivo differentiation of CD11b+ Gr-1+ cells, we provide evidence that αB-crystallin regulates systemic expansion of IMCs through a cell-intrinsic mechanism. Our study suggests a key role of αB-crystaUin in limiting expansion of CD11bα Gr-1α IMCs in diverse pathological conditions. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases ( MMPs) are a large family of proteases involved in many cell-matrix and cell-cell signalling processes through activation, inactivation or release of extracellular matrix ( ECM) and non- ECM molecules, such as growth factors and receptors. Uncontrolled MMP activities underlie the pathophysiology of many disorders. Also matrix metalloproteinase-3 ( MMP-3) or stromelysin-1 contributes to several pathologies, such as cancer, asthma and rheumatoid arthritis, and has also been associated with neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and multiple sclerosis. However, based on defined MMP spatiotemporal expression patterns, the identification of novel candidate molecular targets and in vitro and in vivo studies, a beneficial role for MMPs in CNS physiology and recovery is emerging. The main purpose of this review is to shed light on the recently identified roles of MMP-3 in normal brain development and in plasticity and regeneration after CNS injury and disease. As such, MMP-3 is correlated with neuronal migration and neurite outgrowth and guidance in the developing CNS and contributes to synaptic plasticity and learning in the adult CNS. Moreover, a strict spatiotemporal MMP-3 up-regulation in the injured or diseased CNS might support remyelination and neuroprotection, as well as genesis and migration of stem cells in the damaged brain. [ABSTRACT FROM AUTHOR]

Proteinases have been implicated in the mobilization of haematopoietic progenitor cells (HPCs) from the bone marrow (BM). Here, we report the involvement of the plasminogen (Plg) system in the haematopoietic recovery following chemotherapy. By using gene-deficient mice, we found that plasmin and its activators tPA and uPA play a role in the haematopoietic recovery upon delivery of the cytotoxic agent 5-fluoro-uracil (5-FU). The impaired haematopoietic recovery of Plg-deficient (Plg−/−) mice after 5-FU was not rescued by depletion of fibrinogen, indicating that it was not due to defective fibrinolysis. Instead, loss of Plg impaired breakdown of fibronectin, VCAM-1 and laminin-BM matrix proteins involved in adhesion of HPCs to their BM microenvironment and in transendothelial migration of HPCs. These findings provide novel insights in how plasmin regulates haematopoietic recovery upon cytotoxic myeloablation. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor-D (VEGF-D) is one of the two ligands of the VEGFR-3 receptor on lymphatic endothelial cells. Gene-silencing studies in mice and Xenopus tadpoles recently showed that the role of endogenous VEGF-D in lymphatic development is moderate. By contrast, exogenous VEGF-D is capable of stimulating lymphangiogenesis. Nonetheless, its endogenous role in pathological conditions remains largely unknown. Hence, we reassessed its role in disease, using Vegf-dnull mice. Vegf-dnull mice were generated that, under physiological conditions, displayed normal embryonic and postnatal lymphangiogenesis and lymphatic remodelling, efficient lymphatic functioning and normal health. Vegf-dnull mice also reponded normally in models of skin wound healing and healing of infarcted myocardium, despite enhanced expression of VEGF-D in these models in wild-type mice. In contrast, Vegf-dnull mice displayed reduced peritumoral lymphangiogenesis and lymph node metastasis in an orthotopic pancreatic tumour model. Together, our data indicate that endogenous VEGF-D in mice is dispensible for lymphangiogenesis during development, in postnatal and adult physiology and in several pathological conditions, but significantly contributes to lymphatic metastasis. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Up to now neuroregenerative research mainly focused on improving axonal regrowth, leaving the dendrites, which form an essential component of the neuronal circuit, largely unstudied. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. Here, we postulate the intriguing hypothesis, that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon CNS damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity, recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve crush (ONC) injury, and that the retinal ganglion cell (RGC) dendrites regenerate after axonal repair. This orderly sequence of neurite outgrowth is a recapitulation of development, where axogenesis also precedes dendritogenesis. Strikingly, inhibiting RGC dendritic pruning upon damage perturbed axonal regeneration in zebrafish. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature. In line with this, we observed an increased loss of RGC dendrites and reduced dendritic arbor complexity in the mouse retina when axonal regeneration was induced by inflammatory stimulation. All together, these data point towards a conserved neuronal remodeling mechanism, where dendritic pruning upon neuronal injury supports axonal regeneration. We now hypothesize that a reprogramming and relocation of the neuronal energy production machinery towards the axon is needed for regeneration, a process in which the shrinking dendrites might play a key role. To test this idea, a combination of state‐of‐the‐art in vitro and in vivo research approaches are being pursued. We are characterizing, in the axonal versus dendritic cell compartment, the subcellular and molecular players modulating energy production and enabling axonal regrowth of injured CNS neurons. Overall, our findings could generate pivotal insights into how re‐directing intra‐neuronal energy channelling may promote neuronal repair in the mammalian CNS. [ABSTRACT FROM AUTHOR]

Purpose: In this study, single‐cell transcriptomics was applied to provide insight into cell‐type specific transcriptional dynamics in the neuronal, glial, vascular and inflammatory compartments of the Akimba retina. Investigation of the molecular characteristics and networks underlying the pathobiology of this diabetic retinopathy mouse model might lead to the identification of new pathophysiological or protective mechanisms. Methods: Retinas were isolated from 12‐week‐old Akimba (Ins2AkitaVEGF+/‐) and age‐matched wild type (WT) C57BL/6J mice and dissociated by collagenase treatment into single cell suspension. Single‐cell barcoded libraries were generated (10× Genomics) and sequenced on the Illumina HiSeq4000 platform. After data pre‐processing, principal component analysis‐based clustering was performed, and clusters were annotated based on marker genes. In addition, differential expressed genes between Akimba and WT retinal cells were further analyzed for statistically enriched pathways and categorized for biological function using STRING. Results: Our results showed that neuronal cell death, especially of the rod photoreceptors, is accompanied by an immune response in the Akimba versus WT retina. This is demonstrated by the prominent increase in and activation of resident and invading immune cells and enrichment of e.g. complement, interferon and inflammasome signaling pathways. Transcriptional changes in macroglia point towards their attempt to rescue lost tissue via reactive gliosis, and towards a metabolic shift from glycolysis to oxidative phosphorylation. In addition, the Akimba retina is also characterized by an overall change in ribosome synthesis and translation, oxidative stress responses and metal dyshomeostasis. Conclusion: Our data indicate substantial shifts in abundance of cell types in the Akimba retina, and cell‐specific changes that may lead to functional uncoupling of neuron‐glia interactions. [ABSTRACT FROM AUTHOR]

Excessive post-operative wound healing with subsequent scarring frequently leads to surgical failure of glaucoma filtration surgery (trabeculectomy). We investigated the hypothesis that placental growth factor (PlGF) plays a role in post-operative scar formation, and that it therefore may be a target for improvement of filtration surgery outcome. ELISA experiments showed that PlGF levels were significantly increased in aqueous humour of glaucoma patients and after VEGF treatment, which may indicate an important contribution of this growth factor to wound healing after trabeculectomy. Using a mouse model of glaucoma filtration surgery, we were able to show that intracameral injection of a previously characterized anti-PlGF antibody (ThromboGenics NV) significantly improved surgical outcome by increasing bleb survival and bleb area. This was associated with a significant reduction in post-operative proliferation, inflammation and angiogenesis during the first post-operative days after surgery, and with a decrease in collagen deposition at later stages. Furthermore, inhibition of PlGF seemed to be more effective than anti-VEGF-R2 treatment in improving surgical outcome, possibly via its additional effect on inflammation. These results render PlGF an appealing target for ocular wound healing and point to potential therapeutic benefits of PlGF inhibition for the prevention of surgical failure., (© 2013 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)