Mesenchymal stromal cells (MSCs) are multipotent stem cells that participate in tissue repair and possess considerable immunomodulatory potential. MSCs have been shown to promote allograft survival, yet the mechanisms behind this phenomenon have not been fully defined. Here, we investigate the capacity of MSCs to suppress the allogeneic immune response by secreting the pleiotropic molecule hepatocyte growth factor (HGF). Using an in vivo mouse model of corneal transplantation, we report that MSCs promote graft survival in an HGF-dependent manner. Moreover, our data indicate that topically administered recombinant HGF (a) suppresses antigen-presenting cell maturation in draining lymphoid tissue, (b) limits T-helper type-1 cell generation, (c) decreases inflammatory cell infiltration into grafted tissue, and (d) is itself sufficient to promote transplant survival. These findings have potential translational implications for the development of HGF-based therapeutics. Stem Cells Translational Medicine 2019;8:1030-1040.

Immunotherapy has significantly advanced the field of oncology in recent decades. Understanding normal immunosurveillance, as well as the ways in which tumor cells have evolved to evade it, has provided the knowledge for development of drugs that allow one's own immune system to target and destroy malignant cells (immunotherapy). Cutaneous malignancies are particularly sensitive to this class of drugs. In a very sensitive anatomic region such as the periocular tissue, where surgical excision may come with significant morbidity, this technology has had a strong impact in the successful treatment of historically challenging tumors.

: To perform a systematic review of the application of botulinum toxin A (BTA) in the management of strabismus in the adult and pediatric populations. : A systematic literature search was performed using the Medline database. : In 1989, with the FDA approval of botulinum toxin (onabotulinum toxin A, or BTA) for the treatment of strabismus, patients were provided with an alternative to surgical recession. In this review, we discuss the uses of BTA in the treatment of acute onset comitant esotropia or smaller angle esotropia and as an adjunct to surgery for larger angle esotropia or sixth nerve palsy. Its uses are also explored in intermittent exotropia and vertical strabismus, including thyroid-associated orbitopathy, fourth nerve palsies, and other orbital pathology. : Despite its transient kinetics, BTA can have permanent effects on ocular alignment, promoting binocularity and reduction of diplopia, and can serve as a primary treatment or a muscle sparing option in patients at risk of anterior segment ischemia or need for future surgeries.

Thrombospondin 1 (TSP-1) is an extracellular matrix protein that interacts with a wide array of ligands including cell receptors, growth factors, cytokines and proteases to regulate various physiological and pathological processes. Constitutively expressed by certain ocular surface tissues (e.g. corneal and conjunctival epithelium), TSP-1 expression is modulated during ocular surface inflammation. TSP-1 is an important activator of latent TGF-β, serving to promote the immunomodulatory and wound healing functions of TGF-β. Mounting research has deepened our understanding of how TSP-1 expression (and lack thereof) contributes to ocular surface homeostasis and disease. Here, we review current knowledge of the function of TSP-1 in dry eye disease, ocular allergy, angiogenesis/lymphangiogenesis, corneal transplantation, corneal wound healing and infectious keratitis.

How somatic mutations accumulate in normal cells is poorly understood. A comprehensive analysis of RNA sequencing data from ~6700 samples across 29 normal tissues revealed multiple somatic variants, demonstrating that macroscopic clones can be found in many normal tissues. We found that sun-exposed skin, esophagus, and lung have a higher mutation burden than other tested tissues, which suggests that environmental factors can promote somatic mosaicism. Mutation burden was associated with both age and tissue-specific cell proliferation rate, highlighting that mutations accumulate over both time and number of cell divisions. Finally, normal tissues were found to harbor mutations in known cancer genes and hotspots. This study provides a broad view of macroscopic clonal expansion in human tissues, thus serving as a foundation for associating clonal expansion with environmental factors, aging, and risk of disease.

BACKGROUND: A compelling feature of dry eye disease is that it occurs predominantly in women. We hypothesize that this female prevalence is linked to sex-related differences in the meibomian gland (MG). This gland plays a critical role in maintaining the tear film, and its dysfunction is a major cause of dry eye disease. To understand the factors that underlie MG sexual dimorphism and promote dry eye in women, we seek to identify an optimal model for the human MG. Our goal was to determine whether a murine MG is such a model. Toward that end, we examined whether sex differences in MG gene expression are the same in BALB/c mice and humans. METHODS: Eyelid tissues were collected from humans (n = 5-7/sex) and BALB/c mice (n = 9/sex). MGs were isolated and processed for the evaluation of gene expression by using microarrays and bioinformatics software. RESULTS: Our analysis of the 500 most highly expressed genes from human and mouse MGs showed that only 24.4% were the same. Our comparison of 100 genes with the greatest sex-associated differences in human and mouse MGs demonstrated that none were the same. Sex also exerted a significant impact on numerous ontologies, Kyoto Encyclopedia of Genes and Genomes pathways, and chromosomes, but these effects were primarily species-specific. CONCLUSIONS: Our results indicate that BALB/c mice are not optimal models for understanding sex-related differences in gene expression of the human MG.

PRECIS: Three-dimensional (3D) spectral domain optical coherence tomography (OCT) volume scans of the optic nerve head (ONH) and the peripapillary area are useful in the management of glaucoma in patients with a type I or II Boston Keratoprosthesis (KPro). PURPOSE: The purpose of this study was to report the use of spectral domain OCT in the management of glaucoma in patients with a type I or II Boston KPro. MATERIALS AND METHODS: This study is an observational case series. Four consecutive patients with KPro implants were referred for glaucoma evaluation. A comprehensive eye examination was performed which included disc photography, visual field testing, and high-density spectral domain OCT volume scans of the ONH and the peripapillary area. 2D and 3D parameters were calculated using custom-designed segmentation algorithms developed for glaucoma management. RESULTS: Spectral domain OCT parameters provided useful information in the diagnosis and management of 4 KPro patients. OCT parameters which can be used in KPro patients included 2D retinal nerve fiber layer (RNFL) thickness, 3D peripapillary RNFL volume, 3D peripapillary retinal thickness and volume, 3D cup volume, and 3D neuroretinal rim thickness and volume. In 3 of 4 cases where the traditional 2D RNFL thickness scan was limited by artifacts, 3D spectral domain OCT volume scans provided useful quantitative objective measurements of the ONH and peripapillary region. Therefore, 3D parameters derived from high-density volume scans as well as radial scans of the ONH can be used to overcome the limitations and artifacts associated with 2D RNFL thickness scans. CONCLUSIONS: Spectral domain OCT volume scans offer the possibility to enhance the evaluation of KPro patients with glaucoma by using both 2D and 3D diagnostic parameters that are easily obtained in a clinic setting.

Amblyopia refers to visual impairment resulting from perturbations in visual experience during visual development, typically secondary to strabismus, uncorrected refractive error, and/or deprivation. Amblyopia has traditionally been considered a cortical disease, but the depth of our understanding of this complex neurodevelopmental condition is limited by our ability to appreciate structural pathophysiology in the visual pathway. Recent advances in Optical Coherence Tomography (OCT) have facilitated numerous studies of the structural changes in the retina and optic nerve, thereby expanding our appreciation for the pathogenesis of this condition. In this review, we summarize findings from studies evaluating retinal, retinal nerve fiber layer, and choroidal thickness changes in patients with amblyopia. Focusing on the largest and most recent studies, we discuss common limitations and confounding variables in these studies. We summarize recent advances in ocular imaging technology and reconcile the findings of early histological reports with those of structural OCT in amblyopia.

The presence of optic nerve swelling in pediatric patients is a frequent cause for referral to pediatric ophthalmologists and neuro-ophthalmologists because this finding can be the harbinger of serious neurologic disease including brain tumor, demyelinating disease, infiltrative disease of the optic nerve, or idiopathic intracranial hypertension. Optic nerve head drusen (ONHD) are common and can be particularly difficult to distinguish from true optic nerve swelling in pediatric patients because the ONHD are typically buried beneath the substance of the optic nerve. Correct identification of ONHD is relevant because of the visual morbidity associated with this condition and because of the need to distinguish pseudopapilledema secondary to ONHD from true optic nerve swelling. A variety of imaging modalities may be employed to evaluate for the presence of ONHD, including ultrasound, optical coherence tomography (OCT), enhanced depth imaging-OCT, fluorescein angiography, fundus autofluorescence, and optical coherence tomography angiography. To date, there is no consensus as to which of these techniques is most accurate and which should be part of a standardized evaluation for children suspected of ONHD. This review examines the recent literature analyzing these diagnostic tools and summarizes data regarding best practices for identifying ONHD.

In amyotrophic lateral sclerosis (ALS) spinal motor neurons (SpMN) progressively degenerate while a subset of cranial motor neurons (CrMN) are spared until late stages of the disease. Using a rapid and efficient protocol to differentiate mouse embryonic stem cells (ESC) to SpMNs and CrMNs, we now report that ESC-derived CrMNs accumulate less human (h)SOD1 and insoluble p62 than SpMNs over time. ESC-derived CrMNs have higher proteasome activity to degrade misfolded proteins and are intrinsically more resistant to chemically-induced proteostatic stress than SpMNs. Chemical and genetic activation of the proteasome rescues SpMN sensitivity to proteostatic stress. In agreement, the hSOD1 G93A mouse model reveals that ALS-resistant CrMNs accumulate less insoluble hSOD1 and p62-containing inclusions than SpMNs. Primary-derived ALS-resistant CrMNs are also more resistant than SpMNs to proteostatic stress. Thus, an ESC-based platform has identified a superior capacity to maintain a healthy proteome as a possible mechanism to resist ALS-induced neurodegeneration.