Clinical-Grade Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells Ameliorate Diabetic Retinopathy in db/db Mice

Background aims Mesenchymal stem cells (MSCs) hold great promise in the treatment of diabetic retinopathy (DR) as evidenced by increasing preclinical and clinical studies. However, the absence of standardized and industrialized clinical-grade donor cells hampers the continued development and large-scale clinical application of MSCs-based therapies for DR. Previously, we have identified a unique population of MSCs generated from a clinical-grade human embryonic stem cell (hESC) line under good manufacturing practice conditions that could be a potential source to address the issues. Here, we investigated the therapeutic potential of the clinical-grade hESC line derived MSCs (hESC-MSCs) on db/db mice with DR. Methods The hESC-MSCs were initially characterized by morphological assessment, flow cytometry analysis and trilineage differentiation assays. These cells (5 × 106 cells) were then transplanted intravenously into 12-week-old db/db mice, with phosphate-buffered saline transplantation and untreated groups utilized as controls. The retinal alterations in neural functions and microvascular perfusions, and peripheral blood and retinal inflammatory responses were evaluated at 4- and 6-weeks post-transplantation using electroretinogram (ERG), optical coherence tomography angiography (OCTA) and flow cytometry, respectively. Body weight and fasting blood glucose (FBG) levels were also measured to investigate their systemic implications. Results Compared to controls, intravenous transplantation of hESC-MSCs could significantly: 1) enhance impaired retinal ERG functions (including amplitudes of a-, b-wave and oscillatory potentials) at 4 weeks post-transplantation; 2) alleviate microvascular dysfunctions especially in the inner retina with significance (including reducing non-perfusion area and increasing vascular area density) at 4 weeks post-transplantation; 3) decrease FBG levels at 4 weeks post-transplantation and induce weight loss up to 6 weeks post-transplantation; 4) increase both peripheral blood and retinal IL-10 level at 4 weeks post-transplantation, and modulate peripheral blood inflammatory cytokines and chemokines levels, such as MCP-1 and CXCL1, up to 6 weeks post-transplantation. Conclusions The findings of our study indicated that intravenous transplantation of hESC-MSCs ameliorated retinal neural and microvascular dysfunctions, regulated body weight and FBG, and modulated peripheral blood and retinal inflammation responses in a mouse model of DR. These results suggested that hESC-MSCs could be a potentially effective clinical-grade cell source for the treatment of DR.