Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) have been recognized as a promising cell-free therapy for acute kidney injury (AKI), which avoids safety concerns associated with direct cell engraftment. However, low stability and retention of MSC-EVs have limited their therapeutic efficacy. RGD (Arg-Gly-Asp) peptide binds strongly to integrins, which have been identified on the surface of MSC-EV membranes; yet RGD has not been applied to EV scaffolds to enhance and prolong bioavailability. Here, we developed RGD hydrogels, which we hypothesized could augment MSC-EV efficacy in the treatment of AKI models. In vivo tracking of the labeled EVs revealed that RGD hydrogels increased retention and stability of EVs. Integrin gene knockdown experiments confirmed that EV−hydrogel interaction was mediated by RGD−integrin binding. Upon intrarenal injection into mouse AKI models, EV-RGD hydrogels provided superior rescuing effects to renal function, attenuated histopathological damage, decreased tubular injury, and promoted cell proliferation in early phases of AKI. RGD hydrogels also augmented antifibrotic effects of MSC-EVs in chronic stages. Further analysis revealed that the presence of microRNA let-7a-5p in MSC-EVs served as the mechanism contributing to the reduced cell apoptosis and elevated cell autophagy in AKI. In conclusion, RGD hydrogels facilitated MSC-derived let-7a-5p-containing EVs, improving reparative potential against AKI. This study developed an RGD scaffold to increase the EV integrin-mediated loading and in turn improved therapeutic efficacy in renal repair; therefore this strategy shed light on MSC-EV application as a cell-free treatment for potentiated efficiency.
Bioactive peptides derived from proteins generally need to be folded into secondary structures to activate downstream signaling pathways. However, synthetic peptides typically form random-coils, thus losing their bioactivities. Here, we show that by introducing a self-assembling peptide motif and using different preparation pathways, a peptide from insulin-like growth factor-I (IGF-1) can be folded into an α-helix and β-sheet. The β-sheet one exhibits a low dissociation constant to the IGF-1 receptor (IGF-1R, 11.5 nM), which is only about 3 times higher than that of IGF-1 (4.3 nM). However, the α-helical one and the peptide without selfassembling motif show weak affinities to IGF-1R (K D = 179.1 and 321.6 nM, respectively). At 10 nM, the β-sheet one efficiently activates the IGF-1 downstream pathway, significantly enhancing HUVEC proliferation and preventing cell apoptosis. The β-sheet peptide shows superior performance to IGF-1 in vivo, and it improves ischemic hind-limb salvage by significantly reducing muscle degradation and enhancing limb vascularization. Our study provides a useful strategy to constrain peptides into different conformations, which may lead to the development of supramolecular nanomaterials mimicking biofunctional proteins.
Stem cell therapy has obtained extensive consensus to be an effective method for post myocardial infarction (MI) intervention. Induced pluripotent stem (iPS) cells, which are able to differentiate into multiple cell types, have the potential to generate cardiovascular lineage cells for myocardial repair after ischemic damage, but their poor retention rate significantly hinders the therapeutic efficacy. In the present study, we developed a supramolecular hydrogel which is formed by the self-assembly of folic acid (FA)-modified peptide via a biocompatible method (glutathione reduction) and suitable for cell encapsulation and transplantation. The iPS cells labeled with CM-Dil were transplanted into the MI hearts of mice with or without FA hydrogel encapsulation. The results corroborated that the FA hydrogel significantly improved the retention and survival of iPS cells in MI hearts post injection, leading to augmentation of the therapeutic efficacy of iPS cells including better cardiac function and much less adverse heart remodeling, by subsequent differentiation toward cardiac cells and stimulation of neovascularization. This study reported a novel supramolecular hydrogel based on FA-peptides capable of improving the therapeutic capacity of iPS cells, which held big potential in the treatment of MI.
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