Intraocular pressure reduction and neuroprotection conferred by bone marrow-derived mesenchymal stem cells in an animal model of glaucoma

Abstract

IntroductionGlaucoma is a sight-threatening retinal neuropathy associated with elevated intraocular pressure (IOP) due to degeneration and fibrosis of the trabecular meshwork (TM). Glaucoma medications aim to reduce IOP without targeting the specific TM pathology, Bone-marrow mesenchymal stem cells (MSCs) are used today in various clinical studies. Here, we investigated the potential of MSCs therapy in an glaucoma-like ocular hypertension (OHT) model and decipher in vitro the effects of MSCs on primary human trabecular meshwork cells.MethodsOcular hypertension model was performed by cauterization of 3 episcleral veins (EVC) of Long-Evans male rat eyes. MSCs were isolated from rat bone marrow, amplified in vitro and tagged with quantum dot nanocrystals. Animals were distributed as 1) MSCs group receiving 5.105cells/6μl Minimum Essential Medium and 2) MEM group receiving 6μl MEM (n = 10 each). Injections were performed into the anterior chamber of 20 days-hypertensive eyes and IOP was monitored twice a week for 4 weeks. At the end of experiment, cell distribution in the anterior segment was examined in confocal microscopy on flat mounted corneas. Moreover, we tested in vitro effects of MSCs conditioned medium (MSC-CM) on primary human trabecular meshwork cells (hTM cells) using Akt activation, myosin phosphorylation and TGF-β2-dependent profibrotic phenotype in hTM cells.ResultsWe demonstrated a rapid and long-lasting in vivo effect of MSCs transplantation that significantly reduced IOP in hypertensive eyes induced by EVC. MSCs were located to the ciliary processes and the TM. Enumeration of RGCs on whole flat-mounted retina highlighted a protective effect of MSCs on RGCs death. In vitro, MSC-CM promotes: (i) hTM cells survival by activating the antiapoptotic pathway, Akt, (ii) hTM cells relaxation as analyzed by the decrease in myosin phosphorylation and (iii) inhibition of TGF-β2-dependent profibrotic phenotype acquisition in hTM cells.ConclusionsMSCs injection in the ocular anterior chamber in a rat model of OHT provides neuroprotective effect in the glaucoma pathophysiology via TM protection. These results demonstrate that MSCs constitute promising tool for treating ocular hypertension and retinal cell degeneration.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0168-0) contains supplementary material, which is available to authorized users.

Transplantation of iPSC-derived TM cells rescues glaucoma phenotypes in vivo

“…These cells would represent a convenient source of patient-derived material and secrete growth factors, such as EGF and PDGF, that stimulate TM cell proliferation (44,45). Furthermore, fibroblasts closely resemble mesenchymal stromal cells that have shown promise in laser-induced models of glaucoma (46,47). Our findings indicate that these cells are not inert and improve TM function to some degree.…”

Roles of exosomes in the normal and diseased eye

“…For example, modulation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs), annexins and proteoglycans on exosomes have been shown to increase metastasis (Hakulinen et al, 2008; Sakwe et al, 2011; Stepp et al, 2015; You et al, 2015). This ECM-modulating exosomal activity may also play an important role in eye diseases where pathological ECM remodeling is an integral part of the disease mechanism, such as in glaucoma and AMD (Bowes Rickman et al, 2013; Roy Chowdhury et al, 2015). …”

“…A number of ocular surface diseases involve loss of cells on the surface and endothelium of the cornea (Ahmad, 2012). For all of these ocular diseases, researchers have proposed that stem cell-based therapy could be used to restore tissue health and function (Abu-Hassan et al, 2015; Al-Shamekh and Goldberg, 2014; Erbani et al, 2016; Mead et al, 2015; Nakamura et al, 2016; Roubeix et al, 2015; Zhu et al, 2016). One strategy for replacing lost cells is to transplant stem cells into the affected areas where they differentiate into the desired cell type and restore tissue/organ function (Blenkinsop et al, 2012).…”

Neuroprotection in glaucoma: recent advances and clinical translation

“…14,74,80, 81 The neuroprotective and regenerative effects of MSCs are achieved through their ability to differentiate into neurons and glial cells, promote endogenous neuronal growth, promote neuro/gliogenesis, encourage synaptic connection, reduce demyelination, induce oligodendrogenesis, stimulate angiogenesis, decrease apoptosis, reduce oxidative stress by lowering free radicals, modulate microglial activation and suppress inflammatory responses. They are easy to source from adult bone marrow or human umbilical cord blood, and can be used without immune suppression.…”