Intravenous Delivery of Mesenchymal Stromal Cells Reverses Müller Cell Endoplasmic Reticulum Stress in Diabetic Retinopathy

Background Mesenchymal stromal cells (MSCs) are being extensively studied as a disease-modifying therapy for complications of diabetes mellitus (DM) such as diabetic retinopathy (DR). However, the optimal treatment regimen remains unclear, and challenges persist regarding the timing and route of administration and the mechanisms underlying its effects. This study aimed to investigate the specific role of human umbilical cord-derived mesenchymal stromal cells(hUC-MSCs) in retinal protection, as well as the mechanisms underlying the effects of a single intravenous injection on the pathological alterations of DR. Methods Two time points after the development of diabetes mellitus were chosen for the in vivo experiments to study the effects of the intervention at different disease stages. hUC-MSCs were injected into the tail vein at the 8th and 16th week after STZ injection, and the samples were collected 2 weeks later to observe the therapeutic effect of MSCs on diabetic eye disease. In vitro experiments were conducted using a Müller cell line cultured in a high-glucose environment with hUC-MSCs conditioned media (MSC-CM) to further explore the mechanism of the observed in vivo results. Results After a single intravenous injection of hUC-MSCs at weeks 8 and 16 post-STZ injection, retinal tissue showed improved thickness, particularly in the inner nuclear layer. MSC treatment reduced activation markers (GFAP and Vimentin) of Műller cells and alleviated endoplasmic reticulum (ER) stress. VEGF expression was also reduced in the Műller cells. In summary, MSC-conditioned medium reversed high glucose-induced ER stress and increased expression of VEGF in Műller cells. Conclusions Intravenous injection of hUC-MSC to diabetic animals can alleviate Műller cell activation and ER stress which might represent a therapeutic target for DR.