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Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous systems limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortiums efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.

PurposeThe purpose of this study was to characterize the ability of applied electrical fields (EFs) to direct retinal ganglion cell (RGC) axon growth as well as to assess whether Rho GTPases play a role in translating electrical cues to directional cues.MethodsFull-thickness, early postnatal mouse retina was cultured in electrotaxis chambers and exposed to EFs of varying strengths (50-200 mV/mm). The direction of RGC axon growth was quantified from time-lapsed videos. The rate of axon growth and responsiveness to changes in EF polarity were also assessed. The effect of toxin B, a broad-spectrum inhibitor of Rho GTPase signaling, and Z62954982, a selective inhibitor of Rac1, on EF-directed growth was determined.ResultsIn the absence of an EF, RGC axons demonstrated indiscriminate directional growth from the explant edge. Retinal cultures exposed to an EF of 100 and 200 mV/mm showed markedly asymmetric growth, with 74.2% and 81.2% of axons oriented toward the cathode, respectively (P < 0.001). RGC axons responded to acute changes in EF polarity by redirecting their growth toward the "new" cathode. This galvanotropic effect was partially neutralized by toxin B and Rac1 inhibitor Z62954982.ConclusionsRGC axons exhibit cathode-directed growth in the presence of an EF. This effect is mediated in part by the Rho GTPase signaling cascade.

Failure of central nervous system (CNS) axons to regenerate after injury results in permanent disability. Several molecular neuro-protective and neuro-regenerative strategies have been proposed as potential treatments but do not provide the directional cues needed to direct target-specific axon regeneration. Here, we demonstrate that applying an external guidance cue in the form of electric field stimulation to adult rats after optic nerve crush injury was effective at directing long-distance, target-specific retinal ganglion cell (RGC) axon regeneration to native targets in the diencephalon. Stimulation was performed with asymmetric charged-balanced (ACB) waveforms that are safer than direct current and more effective than traditional, symmetric biphasic waveforms. In addition to partial anatomical restoration, ACB waveforms conferred partial restoration of visual function as measured by pattern electroretinogram recordings and local field potential recordings in the superior colliculus—and did so without the need for genetic manipulation. Our work suggests that exogenous electric field application can override cell-intrinsic and cell-extrinsic barriers to axon regeneration, and that electrical stimulation performed with specific ACB waveforms may be an effective strategy for directing anatomical and functional restoration after CNS injury. [ABSTRACT FROM AUTHOR]

Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGFβ superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin βB (ACTβB), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACTβB inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACTβB and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACTβB and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types.

In developing and self-renewing tissues, terminally differentiated (TD) cell types are typically specified through the actions of multistage cell lineages. Such lineages commonly include a stem cell and multiple progenitor (transit-amplifying) cell stages, which ultimately give rise to TD cells. As the tissue reaches a tightly controlled steady-state size, cells at different lineage stages assume distinct spatial locations within the tissue. Although tissue stratification appears to be genetically specified, the underlying mechanisms that direct tissue lamination are not yet completely understood. Herein, we use modeling and simulations to explore several potential mechanisms that can be utilized to create stratification during developmental or regenerative growth in general systems and in the model system, the olfactory epithelium of mouse. Our results show that tissue stratification can be generated and maintained through controlling spatial distribution of diffusive signaling molecules that regulate the proliferation of each cell type within the lineage. The ability of feedback molecules to stratify a tissue is dependent on a low TD death rate: high death rates decrease tissue lamination. Regulation of the cell cycle lengths of stem cells by feedback signals can lead to transient accumulation of stem cells near the base and apex of tissue.

It is widely accepted that the growth and regeneration of tissues and organs is tightly controlled. Although experimental studies are beginning to reveal molecular mechanisms underlying such control, there is still very little known about the control strategies themselves. Here, we consider how secreted negative feedback factors ("chalones") may be used to control the output of multistage cell lineages, as exemplified by the actions of GDF11 and activin in a self-renewing neural tissue, the mammalian olfactory epithelium (OE). We begin by specifying performance objectives-what, precisely, is being controlled, and to what degree-and go on to calculate how well different types of feedback configurations, feedback sensitivities, and tissue architectures achieve control. Ultimately, we show that many features of the OE-the number of feedback loops, the cellular processes targeted by feedback, even the location of progenitor cells within the tissue-fit with expectations for the best possible control. In so doing, we also show that certain distinctions that are commonly drawn among cells and molecules-such as whether a cell is a stem cell or transit-amplifying cell, or whether a molecule is a growth inhibitor or stimulator-may be the consequences of control, and not a reflection of intrinsic differences in cellular or molecular character.

Studies of developing and self-renewing tissues have shown that differentiated cell types are typically specified through the actions of multistage cell lineages. Such lineages commonly include a stem cell and multiple progenitor (transit amplifying; TA) cell stages, which ultimately give rise to terminally differentiated (TD) cells. In several cases, self-renewal and differentiation of stem and progenitor cells within such lineages have been shown to be under feedback regulation. Together, the existence of multiple cell stages within a lineage and complex feedback regulation are thought to confer upon a tissue the ability to autoregulate development and regeneration, in terms of both cell number (total tissue volume) and cell identity (the proportions of different cell types, especially TD cells, within the tissue). In this paper, we model neurogenesis in the olfactory epithelium (OE) of the mouse, a system in which the lineage stages and mediators of feedback regulation that govern the generation of terminally differentiated olfactory receptor neurons (ORNs) have been the subject of much experimental work. Here we report on the existence and uniqueness of steady states in this system, as well as local and global stability of these steady states. In particular, we identify parameter conditions for the stability of the system when negative feedback loops are represented either as Hill functions, or in more general terms. Our results suggest that two factors -- autoregulation of the proliferation of transit amplifying (TA) progenitor cells, and a low death rate of TD cells -- enhance the stability of this system.

Purpose: To assess the accuracy of radiographic interpretation between the clinician and radiologist when compared to histopathology of orbital lesions. Methods: A retrospective chart review of patients at the University of California Davis Eye Center who underwent orbitotomy from 1/1/2000 to 5/22/2019 was performed. Charts with a preoperative imaging report, preoperative clinical assessment including the clinician's interpretation of imaging, and histopathologic diagnosis were included. The specific diagnoses were grouped into related classes of pathology for the analysis. The clinical and radiologic assessments were compared against the final histopathologic diagnosis for concordance. A concordance analysis was performed. Results: 242 patients (mean age 49 years, 53.5% female) were reviewed. Of these records 185 documented the clinician's clinical impression, the radiology report, as well as the histopathology report. The clinician's preoperative assessment had substantial agreement [kappa = 0.72 (0.65,0.79)] with the final histopathologic result and was correct in 75.7% (140/185) of cases whereas the radiology report was correct in 52.4% (97/185) with a moderate level of agreement [kappa = 0.47 (0.39, 0.55)]. In 49.2% (91/185) of cases the final histopathology correlated with both the clinical impression and radiology report [kappa = 0.58 (0.55, 0.61)]. Conclusions: The accurate interpretation of orbital imaging is a challenge and histopathologic examination remains the gold standard for diagnosis. While orbital imaging is a valuable diagnostic tool the interpretation of these studies is most accurate when conducted in the context of the patient's medical history, clinical exam, and with the physician most familiar with various orbital lesions. [ABSTRACT FROM AUTHOR]

Background and Objectives: It is commonly taught that thyroid eye disease (TED) causes enlargement of the extraocular muscles (EOMs) in the following descending order: inferior rectus (IR), medial rectus (MR), superior rectus (SR), lateral rectus (LR), superior oblique (SO) and inferior oblique (IO). However, with recent literature challenging this notion, we aimed to compare EOM volumes in our cohort of TED patients.  Methods: We conducted a retrospective, non-randomized case-control study. Twenty-eight orbits from 28 unique patients with TED who had high-resolution CT scans were compared to 31 normal orbits, all from a single academic institution. Orbital soft tissues were manually segmented using ITK-SNAP 3.8.0 (http://itksnap.org), and soft tissue volumes of the control and TED orbits were compared using independent-sample t-tests., Results: Of the TED orbits, 54% of SR/levator palpebrae superioris complex volumes (SRC) and 50% of IR volumes were greater than two standard deviations above the normal orbit average. Compared to controls, the mean SRC volume in TED subjects was 2.3 times enlarged, followed by the IR (2.1 times), SO (1.8 times), MR (1.7 times), LR (1.6 times), IO (1.6 times), and orbital fat (1.4 times) ( p < 0.01 for all).  Conclusions: Our findings suggest that contrary to previous teaching, the SRC may be the most severely affected in TED., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Review Board (IRB) of the University of Southern California issued approval (HS-20-00911). Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: Unrestricted grant to the Department of Ophthalmology from Research to Prevent Blindness, New York, NY. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Park et al.)

Competing Interests: The authors report no conflicts of interest.

Objectives: Giant cell arteritis (GCA) is a vasculitis that affects large and medium sized arteries. The aetiology of GCA is unknown and numerous risk factors have been proposed. In this article, we evaluate the incidence of biopsy-positive GCA in Northern California and assess for seasonal variation., Methods: We performed a retrospective review based on billing codes of temporal artery biopsies performed at the University of California, Davis from 2003 to 2014., Results: We identified 174 biopsies (119 female, 55 male). Of these, 21 positive biopsies were female while 8 were male. Although three times as many women had a positive biopsy compared to men, twice as many biopsies were performed on women. Women were not found to have a significantly higher risk of developing GCA over men. Patients with a positive biopsy averaged 76.4±8.9 years of age. The odds of having a positive biopsy increased significantly with age. Positive biopsies were significantly more likely to occur in the months of May through July than the rest of the year (p<0.028)., Conclusions: Our retrospective study is the first report of the seasonal incidence of biopsy-proven GCA in California. Our data suggest that increased age and summer months are risk factors for developing biopsy-proven GCA in our region.