Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase β-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and β-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/β-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.

Mesenchymal stem cells (MSCs) have been widely applied to regenerative medicine owing to their multiple differentiation, self-renewal, and immunomodulatory abilities. Exosomes are cell-secreted natural nanovesicles and thought to be mediators of intercellular communication and material transport. The therapeutic potential of MSCs can be largely attributed to MSC-derived exosomes (MSC-exosomes). Emerging evidence suggests that the therapeutic efficacy of MSC-exosomes is highly dependent on the status of MSCs, and optimization of the extracellular environment affects the exosomal content. Pretreatment methods including three-dimensional cultures, hypoxia, and other biochemical cues have been shown to potentially enhance the biological activity of MSC-exosomes while maintaining or enhancing their production. On the other hand, engineering means to enhance the desired function of MSC-exosomes has been rapidly gaining attention. In particular, biologically active molecule encapsulation and membrane modification can alter or enhance biological functions and targeting of MSC-exosomes. In this review, we summarize two possible strategies to improve the therapeutic activity of MSC-exosomes: preconditioning approaches and engineering exosomes. We also explore the underlying mechanisms of different strategies and discuss their advantages and limitations of the upcoming clinical applications.

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.

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As a novel cell-free strategy, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) inherit the therapeutic potential of donor cells, and are widely used for the treatment of many diseases. Increasing studies have shown that MSC-EVs transfer various bioactive molecules to create a beneficial microenvironment, thus exerting protective roles in diabetic mellitus (DM) and diabetic complications. To overcome the limitations of natural MSC-EVs such as heterogeneity and insufficient function, several modification methods have been established for constructing engineered MSC-EVs with elevated repairing efficiency. In this review, the PubMed library was searched from inception to August 2022, using a combination of Medical Subject Headings (MeSH) and keywords related to MSC-EVs, DM, and diabetic complications. We provide an overview of the major characteristics of MSC-EVs and summarize the recent advances of MSC-EV-based therapy for hyperglycemia-induced tissue damage with an emphasis on MSC-EV-mediated delivery of functional components. Moreover, the potential applications of engineered MSC-EVs in DM-related diseases therapy are discussed by presenting examples, and the opportunities and challenges for the clinical translation of MSC-EVs, especially engineered MSC-EVs, are evaluated.