Subretinal Transplantation of Human Amniotic Epithelial Cells in the Treatment of Autoimmune Uveitis in Rats

Abstract

As a featured ocular inflammatory disease, autoimmune uveitis is the major cause of blindness in the clinic. Although current immunosuppressive regimens can alleviate the progression of autoimmune uveitis, they have serious side effects. Therefore, an alternative therapeutic strategy is urgently required. The present study investigated the therapeutic efficacy of human amniotic epithelial cells (hAECs) on autoimmune uveitis in a rat model. Herein, experimental autoimmune uveitis (EAU) was induced in rats via a subcutaneous injection of interphotoreceptor retinoid-binding protein. EAU rats were treated with hAECs or the vehicle solution via a subretinal injection on day 0 and day 6 after immunization, and rats were sacrificed on day 12 and day 18 for further analysis. The pathological development of EAU was evaluated by slit lamp microscopy. Immune cell infiltration and retinal structure damage were examined by histological examination of hematoxylin and eosin (H&E) and immunofluorescence staining. T-cell subsets were detected by flow cytometry, and the levels of inflammatory cytokines were quantified by enzyme-linked immunosorbent assay (ELISA). hAEC treatment ameliorated the pathological progression of EAU and preserved the retinal structure organization and thickness, especially in the preventive group that received a subretinal injection on day 0. Moreover, hAECs inhibited the retinal infiltration of macrophages and T-cells. Mechanistically, hAECs modulated the balance of T-cell subsets by downregulating T helper (Th)17 cells and upregulating T regulatory (Treg) cells, as confirmed by decreased interleukin (IL)-17 and increased IL-10 levels in the spleens and lymph nodes of EAU rats. Furthermore, hAECs improved the local cytokine environment in EAU rats by suppressing the monocyte chemoattractant protein (MCP)-1, IL-17 and interferon (IFN)-γ levels and enhancing the IL-10 in the aqueous humor. Therefore, subretinal transplantation of hAECs in EAU rats ameliorated ocular inflammation, preserved the retinal structure and coordinated the immune balance. The current study provides a novel therapeutic strategy for autoimmune uveitis and related ocular inflammatory diseases in the clinic.

Human Amniotic Epithelial Stem Cells: A Promising Seed Cell for Clinical Applications

“…It is rather complicated to illustrate the deep mechanisms by which hAESCs suppress an excessive immune response. It was reported that hAESCs are capable of preventing macrophage and T cell infiltration into the lesion area and maintaining the proper portions of different T cell subtypes by modulating the cytokine concentration inside the microenvironment in certain autoimmune disorder models [ 134 , 135 ]. Actually, previous research has focused on the anti-inflammation effects of conditioned medium and cytokines from hAESCs.…”

“…The latter is considered to be a pivotal subtype in inhibiting inflammation and encouraging tissue repair. Three types of cytokines related to anti-inflammation have been proven to be produced by hAESCs and amniotic tissue: (1) apoptosis inducers such as tumor necrosis factor-α (TNF-α), Fas ligand (FasL), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL); (2) macrophage migration inhibitors such as transforming growth factor-β (TGF-β) and macrophage migration-inhibitory factor (MIF); and (3) other antiangiogenic and anti-inflammatory proteins including interleukin-1 receptor antagonist (IL-1ra), interleukin-10 (IL-10), tissue inhibitors of metalloproteinase (TIMPs), collagen XVⅢ, and thrombopondin-1 [ 134 , 135 , 136 , 137 , 138 ]. Data indicate that these cytokines are critical in the hAESC- and amniotic-tissue-mediated anti-inflammation process.…”

“…Based on their plasticity and immunomodulatory properties, hAESCs have been considered for treatment of a broad variety of conditions, including lung fibrosis [ 40 , 115 , 131 , 149 , 151 , 152 , 153 , 154 ], spinal cord injuries [ 60 ], Parkinson’s disease [ 64 ], Alzheimer’s disease [ 155 ], diabetes [ 69 ], wound healing [ 147 , 148 , 156 ], liver fibrosis [ 75 , 157 , 158 , 159 ], autoimmune uveitis [ 135 ], Hashimoto’s thyroiditis and systemic lupus erythematosus [ 134 ], and intrauterine adhesions [ 160 , 161 , 162 ]. Among these preclinical trials involving hAESCs, autoimmune diseases make up a large proportion, presumably because of the tremendous effect of immunomodulation.…”

“…Similarly, hAESCs modulate the balance of TH17 and Treg cells in experimental autoimmune thyroiditis (EAT) and systemic lupus erythematosus (SLE) mice. In addition, hAESCs improved cytokine environment by inhibiting IL-17 A and IFN-γ and enhancing TGF-β [ 134 ]. In a word, hAESCs represent a great potential therapeutic strategy against immune diseases in light of their immunoregulatory ability.…”

Hyaluronic acid ameliorates the proliferative ability of human amniotic epithelial cells through activation of TGF-β/BMP signaling

“…Unlike human ESCs, hAECs do not express telomerase and thus are not tumorigenic upon transplantation (Miki, 2018). Based on these excellent properties, hAECs have been widely applied in the pre-clinical treatment of many diseases, e.g., liver cirrhosis (Lin et al, 2015), pulmonary damages (Zhu et al, 2017), neurological disorders (Sankar & Muthusamy, 2003), autoimmune uveitis (Li et al, 2018), diabetes (Luo et al, 2019), early Achilles tendon defects (Barboni et al, 2018), as well as aging-related diseases (Di Germanio et al, 2016). Therefore, hAECs possess considerable therapeutic potentials in regenerative medicine.…”