Abstract
Glaucoma is a multifactorial syndrome in which the development of pro-apoptotic signals are the causes for retinal ganglion cell (RGC) loss. Most of the research progress in the glaucoma field have been based on experimentally inducible glaucoma animal models, which provided results about RGC loss after either the crash of the optic nerve or IOP elevation. In addition, there are genetically modified mouse models (DBA/2J), which make the study of hereditary forms of glaucoma possible. However, these approaches have not been able to identify all the molecular mechanisms characterizing glaucoma, possibly due to the disadvantages and limits related to the use of animals. In fact, the results obtained with small animals (i.e., rodents), which are the most commonly used, are often not aligned with human conditions due to their low degree of similarity with the human eye anatomy. Although the results obtained from non-human primates are in line with human conditions, they are little used for the study of glaucoma and its outcomes at cellular level due to their costs and their poor ease of handling. In this regard, according to at least two of the 3Rs principles, there is a need for reliable human-based in vitro models to better clarify the mechanisms involved in disease progression, and possibly to broaden the scope of the results so far obtained with animal models. The proper selection of an in vitro model with a “closer to in vivo” microenvironment and structure, for instance, allows for the identification of the biomarkers involved in the early stages of glaucoma and contributes to the development of new therapeutic approaches. This review summarizes the most recent findings in the glaucoma field through the use of human two- and three-dimensional cultures. In particular, it focuses on the role of the scaffold and the use of bioreactors in preserving the physiological relevance of in vivo conditions of the human trabecular meshwork cells in three-dimensional cultures. Moreover, data from these studies also highlight the pivotal role of oxidative stress in promoting the production of trabecular meshwork-derived pro-apoptotic signals, which are one of the first marks of trabecular meshwork damage. The resulting loss of barrier function, increase of intraocular pressure, as well the promotion of neuroinflammation and neurodegeneration are listed as the main features of glaucoma. Therefore, a better understanding of the first molecular events, which trigger the glaucoma cascade, allows the identification of new targets for an early neuroprotective therapeutic approach.
Highlights
Primary open angle glaucoma (POAG) is a chronic disease that leads to retinal ganglion cell (RGC) loss and, the characteristic cupping of the papilla at the optic nerve level.In spite of the fact that it has been known since the time of Hippocrates, many aspects of this disease still remain obscure.The only therapy recognized to be useful for glaucoma treatment is the lowering of intraocular pressure (IOP) the exact relationships between IOP elevation and the optic nerve head (ONH) degeneration, which leads to visual field alteration, have not been understood yet
It is known that the direct effects of the oxidative stress (OS) injury underlying the POAG onset seem to be linked in particular with trabecular meshwork (TM) damage, which is responsible for the increase in IOP in glaucomatous eyes [26,27,28,29]
Given the crucial role of TM in conventional outflow pathway regulation, it has been hypothesized that glaucomatous TM could be involved in RGC death through the release of molecular signals harmful for RGC
Summary
Primary open angle glaucoma (POAG) is a chronic disease that leads to retinal ganglion cell (RGC) loss and, the characteristic cupping of the papilla at the optic nerve level.In spite of the fact that it has been known since the time of Hippocrates, many aspects of this disease still remain obscure.The only therapy recognized to be useful for glaucoma treatment is the lowering of intraocular pressure (IOP) the exact relationships between IOP elevation and the optic nerve head (ONH) degeneration, which leads to visual field alteration, have not been understood yet. Primary open angle glaucoma (POAG) is a chronic disease that leads to retinal ganglion cell (RGC) loss and, the characteristic cupping of the papilla at the optic nerve level. IOP reduction alone is not always enough for slowing-down blindness progression [1, 2]. Many molecular mechanisms such as the ones involved in glaucoma etiology have been recognized, and in this regard, a wide range of substances with action either on a specific target or on multiple targets have been discovered [3]. Neuroprotection, neurodegeneration, and neuroenhancement have gained great importance over time because such approaches prevent RGCs from death and repair or regenerate the cell damage, changing the course of the disease [4]
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