The Future of Stem Cells and Their Derivates in the Treatment of Glaucoma. A Critical Point of View

Abstract

This review focuses on the clinical translation of preclinical studies, especially those that have used stem cells in the treatment of glaucoma, with an emphasis on optic nerve regeneration. The studies referred to in the review aim to treat optic nerve atrophy, while cell therapies targeting other sites in the eye, such as the trabecular meshwork, have not been addressed. Such complex and varied pathophysiological mechanisms that lead to glaucoma may explain the fact that although stem cells have a high capacity of neuronal regeneration, the treatments performed did not have the expected results and the promise offered by animal studies was not achieved. By analyzing the facts associated with failure, important lessons are to be learned: the type of stem cells that are used, the route of administration, the selection of patients eligible for these treatments, additional therapies that support stem cells transplantation and their mode of action, methods of avoiding the host’s immune response. Many of these problems could be solved using exosomes (EV), but also miRNA, which allows more targeted approaches with minimal side effects.

Optic Neuritis in Multiple Sclerosis—A Review of Molecular Mechanisms Involved in the Degenerative Process

“…Digitalization and technological advances over the last decade have enabled the discovery of new immunosuppressive agents and the development of monoclonal antibodies which, when administered, induce a superior therapeutic response and thus improve patient prognosis [ 176 ]. Mesenchymal stem cell therapy is a promising research direction, with promising clinical results in small group clinical trials [ 191 , 192 , 193 ]. This therapy has an anti-inflammatory effect and potentiates remyelination, but it is limited in its use in terms of identifying the anatomical site of the lesion in the optic nerve or retina [ 194 ].…”

Evaluation of neuroprotective and immunomodulatory properties of mesenchymal stem cells in an ex vivo retinal explant model

“…This swelling of the explants may correspond to the adverse effects reported in clinical trials in humans. Indeed, despite promising results in animals with good efficacy and good safety profiles, the translation to humans in clinical trials was more than disappointing [ 25 ]. Several studies and trials have warned of serious ocular adverse effects following MSC transplantation, questioning the safety of using MSCs in retinal disease [ 44 – 46 ].…”

“…More recently, other stem cell-free approaches using extracellular vesicles (exosomes and microvesicles), have been under investigation. These vesicles are considered to be responsible for the paracrine effects of MSCs, promoting immunomodulation, tissue repair, and regeneration, with a lower risk of oncogenic transformation and immune reactions than injections of whole MSCs [ 25 , 61 – 63 ].…”

“…Several M2 phenotype markers characterize this M2 state, e.g., the enzyme Arginase 1 (ARG1), a marker of microglia involved in tissue repair and phagocytosis, the receptor CD163, a marker of microglia implicated in the anti-inflammatory process and healing, IL-10, an anti-inflammatory cytokine used by the M2 subtype to antagonize the pro-inflammatory phase and healing, and TNFα-stimulated gene-6 (TSG-6/TNFAIP6), which is a key anti-inflammatory factor produced by MSCs [ 19 – 22 ]. Reducing the pro-inflammatory M1 phenotype or inducing M2 microglial polarization might represent a potential and promising therapeutic option to treat neuroinflammatory degenerative diseases such as glaucoma [ 9 , 23 – 25 ]. Among potent immunomodulators of microglial polarization, MSCs possess potent immunoregulatory properties and might inhibit a harmful inflammatory reaction in the diseased retina [ 2 , 25 , 26 ].…”

“…Reducing the pro-inflammatory M1 phenotype or inducing M2 microglial polarization might represent a potential and promising therapeutic option to treat neuroinflammatory degenerative diseases such as glaucoma [ 9 , 23 – 25 ]. Among potent immunomodulators of microglial polarization, MSCs possess potent immunoregulatory properties and might inhibit a harmful inflammatory reaction in the diseased retina [ 2 , 25 , 26 ].…”