A limbal stem cell deficiency murine model with residual limbal stem cells.

Bilateral limbal stem cell deficiency (LSCD) is a significant cause of corneal blindness and is more difficult to treat, as compared with unilateral LSCD because no source of autologous limbal stem cells (LSCs) remains in these patients. Thus, bilateral patients could be candidates for treatment with allogeneic LSC transplants that require long-term systemic immunosuppression therapy. Thus, if possible, for the correct candidates, using autologous LSCs could be a preferred treatment.

Retinal microglia exacerbate uveitis by functioning as local antigen-presenting cells.

Autoimmune uveitis is a major cause of blindness in the working-age population of developed countries. Experimental autoimmune uveitis (EAU) depends on activation of interphotoreceptor retinoid-binding protein (IRBP) specific CD4 effector T cells that migrate systemically and infiltrate into the retina. Following systemic induction of retinal antigen-specific T cells, the development of EAU can be broken down into three phases: early phase when inflammatory cells begin to infiltrate the retina, amplification phase, and peak phase.

The Role of Epigenetics in Accelerated Aging: A Reconsideration of Later-Life Visual Loss After Early Optic Neuropathy.

Background: In 2005, we reported 3 patients with bilateral optic nerve damage early in life. These patients had stable vision for decades but then experienced significant bilateral vision loss with no obvious cause. Our hypothesis, novel at that time, was that the late decline of vision was due to age-related attrition of retinal ganglion cells superimposed on a reduced neuronal population due to the earlier injury.

Microglia preserve visual function loss in the aging retina by supporting retinal pigment epithelial health.

Background: Increased age is a risk factor for the development and progression of retinal diseases including age-related macular degeneration (AMD). Understanding the changes that occur in the eye due to aging is important in enhancing our understanding of AMD pathogenesis and the development of novel AMD therapies. Microglia, the resident brain and retinal immune cells are associated with both maintaining homeostasis and protection of neurons and loss of microglia homeostasis could be a significant player in age related neurodegeneration.

Opposing Roles of Blood-Borne Monocytes and Tissue-Resident Macrophages in Limbal Stem Cell Damage after Ocular Injury.

Limbal stem cell (LSC) deficiency is a frequent and severe complication after chemical injury to the eye. Previous studies have assumed this is mediated directly by the caustic agent. Here we show that LSC damage occurs through immune cell mediators, even without direct injury to LSCs.

Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation.

Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma.

Unlabelled: Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma.

High expression of SARS-CoV2 viral entry-related proteins in human limbal stem cells.

Purpose: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). While the ocular surface is considered one of the major SARS-CoV2 transmission routes, the specific cellular tropism of SARS-CoV2 is not fully understood. In the current study, we evaluated the expression and regulation of two SARS-CoV2 viral entry proteins, TMPRSS2 and ACE2, in human ocular epithelial cells and stem cells.

Reprogramming to recover youthful epigenetic information and restore vision.

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity. Changes to DNA methylation patterns over time form the basis of ageing clocks, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known.

Investigation of factors associated with ABCB5-positive limbal stem cell isolation yields from human donors.

Purpose: To identify factors associated with isolation yields of ATP-binding cassette (ABC) superfamily member B5 (ABCB5)-positive limbal stem cells (LSCs) from human cadaveric donor eyes.

Methods: Whole eye globes were obtained from the Saving Sight eye bank, Kansas City, MO and the CorneaGen eye bank, Seattle, WA. ABCB5-positive LSCs were sorted by flow cytometry upon anti-ABCB5 monoclonal antibody staining within one week after donor death.

Retinal microglia initiate neuroinflammation in ocular autoimmunity.

Autoimmune uveitis is a sight-threatening ocular inflammatory condition in which the retina and uveal tissues become a target of autoreactive immune cells. While microglia have been studied extensively in autoimmune uveitis, their exact function remains uncertain. The objective of the current study was to determine whether resident microglia are necessary and sufficient to initiate and amplify retinal inflammation in autoimmune uveitis.

Proceedings of the Association for Research in Vision and Ophthalmology and Champalimaud Foundation Ocular Oncogenesis and Oncology Conference.

The 2018 Ocular Oncogenesis and Oncology Conference was held through a partnership of the Association for Research in Vision and Ophthalmology (ARVO) and the Champalimaud Foundation. Twenty-one experts from international ocular oncology centers, from the Champalimaud Clinical Centre and the Champalimaud Foundation Cancer Research Program, and from patient advocacy organizations, delivered lectures on subjects that ranged from global ocular oncology, to basic research in mechanisms of ocular malignancy, to clinical research in ocular cancers, and to anticipated future developments in the area. The scientific program of the conference covered a broad range of ocular tumors-including uveal melanoma, retinoblastoma, ocular surface tumors, and adnexal and intraocular lymphomas-and pathogenesis and management were deliberated in the context of the broader systemic cancer discipline.

Soluble Fas ligand blocks destructive corneal inflammation in mouse models of corneal epithelial debridement and LPS induced keratitis.

Neutrophil-mediated inflammation plays a critical role in corneal damage following injury or infection. Previous studies demonstrated that membrane-bound FasL (mFasL) induces neutrophil chemokine production. However, the extracellular domain of mFasL is normally cleaved by matrix metalloproteinases to release a soluble form of FasL (sFasL) and sFasL antagonizes mFasL-mediated chemokine production.