Abstract
Glaucoma is characterized by progressive, irreversible damage to the retinal ganglion cells (RGCs) and their axons. Our previous study has shown that the intravitreal transplantation of human umbilical cord mesenchymal stem cells (hUC-MSCs) reveals a neuroprotective role in microsphere injection-induced ocular hypertension (OHT) rat models. The protection is related to the modulation of glial cells, but the mechanisms are still unknown. The purpose of the present study is to clarify the potential neuroinflammatory mechanisms involved in the neuroprotective role of hUC-MSCs. OHT models were established with SD rats through intracameral injection of polystyrene microbeads. The animals were randomly divided into three groups: the normal group, the OHT+phosphate-buffered saline (PBS) group, and the OHT+hUC-MSC group. Retinal morphology was evaluated by measuring the inner retinal thickness via optical coherence tomography (OCT). Retinal cell apoptosis was examined by TUNEL staining and Bax expression 14 days following hUC-MSC transplantation. The expression levels of glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (iba-1), and toll-like receptor 4 (TLR4) were assessed via immunohistochemistry, real-time quantitative PCR, and Western blot. RNA and proteins were extracted 14 days following transplantation, and the expression levels of the TLR4 signaling pathways and proinflammatory cytokines—myeloid differentiation factor 88 (MyD88), IL-1β, IL-6, and TNF-α—were determined. OCT showed that the intravitreal transplantation of hUC-MSCs significantly increased the inner thickness of the retina. A TUNEL assay and the expression of Bax suggested that the apoptosis of retinal cells was decreased by hUC-MSCs 14 days following transplantation. Intravitreal hUC-MSC transplantation resulted in a decreased expression of GFAP, iba-1, TLR4, MyD88, IL-1β, IL-6, and TNF-α 14 days following transplantation. In addition, via in vitro experiments, we found that the increased expression of the TLR4 signaling pathway induced by lipopolysaccharide (LPS) was markedly decreased after hUC-MSCs were cocultured with rMC-1 and BV2 cells. These findings indicate that hUC-MSC transplantation attenuates OHT-induced retinal neuroinflammation via the TLR4 pathway.
Highlights
Glaucoma is characterized by progressive, irreversible damage to the retinal ganglion cells (RGCs) and their axons [1]
We examined whether hUC-mesenchymal stem cells (MSCs) could modulate toll-like receptor 4 (TLR4) pathway-related agents and proinflammatory cytokine levels in rMC-1 cells. rMC-1 cells stimulated with LPS demonstrated increased glial fibrillary acidic protein (GFAP) (P = 0:0174) and TLR4 (P < 0:0001) expression compared with the control cells, and TLR4 was colocalized in GFAP
Considered together, these results indicate that the amelioration of retinal neuroinflammation by hUC-MSC transplantation may be relevant to attenuating neuroinflammatory response via modulating glial cells and TLR4 signaling pathways, possibly indicating a novel repair mechanism in hUC-MSCs (Figure 9)
Summary
Glaucoma is characterized by progressive, irreversible damage to the retinal ganglion cells (RGCs) and their axons [1]. Glaucoma is an age-related multifactorial neurodegenerative disease, the most common risk factor of which is elevated intraocular pressure (IOP). An increasing number of literatures have suggested that neuroinflammation is a vital process in glaucoma [3,4,5,6]. Glial cells are recognized as playing vital immunological roles within the retina, and their participation in glaucoma progression has been reported [8, 9]. Formichella et al found that astrocyte reactivity occurs both in glaucomatous retina and retina with glaucoma risk factors [10].
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