Mesenchymal stem cells-derived small extracellular vesicles alleviate diabetic retinopathy by delivering NEDD4

Abstract

Background As a leading cause of vision decline and severe blindness in adults, diabetic retinopathy (DR) is characterized by the aggravation of retinal oxidative stress and apoptosis in the early stage. Emerging studies reveal that mesenchymal stem cells-derived small extracellular vesicles (MSC-sEV) treatment represents a promising cell-free approach to alleviate ocular disorders. However, the repairing effects of MSC-sEV in DR remain largely unclear. This study aimed at exploring the role and the underlying mechanism of MSC-sEV in hyperglycemia-induced retinal degeneration. Methods In vivo, we used streptozotocin (STZ) to establish diabetic rat model, followed by the intravitreal injection of MSC-sEV to determine the curative effect. The cell viability and antioxidant capacity of retinal pigment epithelium (RPE) cells stimulated with high-glucose (HG) medium after MSC-sEV treatment were analyzed in vitro. By detecting the response of cell signaling pathways in MSC-sEV-treated RPE cells, we explored the functional mechanism of MSC-sEV. Mass spectrometry was performed to reveal the bioactive protein which mediated the role of MSC-sEV. Results The intravitreal injection of MSC-sEV elicited antioxidant effects and counteracted retinal apoptosis in STZ-induced DR rat model. MSC-sEV treatment also reduced the oxidative level and enhanced the proliferation ability of RPE cells cultured in HG conditions in vitro. Further studies showed that the increased level of phosphatase and tensin homolog (PTEN) inhibited AKT phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2) expression in RPE cells stimulated with HG medium, which could be reversed by MSC-sEV intervention. Through mass spectrometry, we illustrated that MSC-sEV-delivered neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) could cause PTEN ubiquitination and degradation, activate AKT signaling and upregulate NRF2 level to prevent DR progress. Moreover, NEDD4 knockdown impaired MSC-sEV-mediated retinal therapeutic effects. Conclusions Our findings indicated that MSC-sEV ameliorated DR through NEDD4-induced regulation on PTEN/AKT/NRF2 signaling pathway, thus revealing the efficiency and mechanism of MSC-sEV-based retinal protection and providing new insights into the treatment of DR.

Mesenchymal stem cell‐derived extracellular vesicles for metabolic syndrome therapy: Assessing efficacy with nuclear magnetic resonance spectroscopy

“…Figure 2 illustrates the basic process of obtaining MSC-EVs and also their applications in MetS. Table 1 summarises the comprehensive studies conducted in either vitro or vivo that revealed the potential of MSC-EVs therapy in normalising metabolic parameters of MetS subjects [15][16][17][18][19][20][21] ; These studies demonstrate that MSC-EVs derived from various sources possess the ability to promote cell proliferation, migration and multipotent differentiation.…”

“…MSC-EVs efficacy in MetS, such as hypertension, diabetic retinopathy, renal damage, fatty liver disease and diabetes mellitus have been demonstrated in many studies. [15][16][17][18][19][20][21] MSCs, mesenchymal stem cells; MSC-EV, MSCs derived extracellular vesicles; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis.…”

“…T A B L E 1 Summary of significant metabolome changes of previous studies targeting metabolic syndrome using MSC-EV therapy. [15][16][17][18][19][20][21] Disease models excessive alcohol intake, adherence to Western dietary patterns, low levels of cardiorespiratory fitness, as well as the use of antiretroviral drugs and atypical antipsychotic drugs. 22 analyses.…”

“…MSC‐EVs are isolated from MSC cell culture and could be administered into disease study subjects. MSC‐EVs efficacy in MetS, such as hypertension, diabetic retinopathy, renal damage, fatty liver disease and diabetes mellitus have been demonstrated in many studies 15–21 …”

Mesenchymal Stem Cell-Derived Extracellular Vesicles: A Potential Therapy for Diabetes Mellitus and Diabetic Complications

“…In recent years, researchers have focused on the exploration of functional components within MSC-EVs in diabetic retinopathy therapy. For example, the results of Sun et al have shown that hyperglycemia-induced upregulation of phosphatase and tensin homolog (PTEN) can inhibit AKT phosphorylation and nuclear factor erythroid 2-related factor 2 (NRF2) expression in retinal tissues, whereas MSC-EVs ameliorate retinal apoptosis and oxidative stress by transporting neuronal precursor cell-expressed developmentally downregulated 4 (NEDD4) to cause PTEN ubiquitination and degradation and activate downstream AKT/NRF2 pathway [ 95 ]. The knockdown of NEDD4 significantly impairs the retinal protective potential of MSC-EVs.…”