Supramolecular Nanofibers Containing Arginine-Glycine-Aspartate (RGD) Peptides Boost Therapeutic Efficacy of Extracellular Vesicles in Kidney Repair

Abstract

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.

Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases

“…Demonstrably, RGD hydrogels interact with EVs mediating by integrin subunits αv, β3, and β8 [41]. Besides slowing the eliminating process of EVs, encapsulation can assist EVs kidney to attenuate kidney injury by pathological damage reduction, promotion of cell proliferation, inhibition of renal cell apoptosis, amplification of autophagic activation, and enhancing of angiogenesis as well as ameliorating fibrosis [39][40][41]. It is also found the overexpression of Oct-4 can improve the therapeutic effect of MSC-EVs [42], and hypoxia stimulates the MSCs to secrete more EVs [43].…”

“…However, the low retention and poor stability of EVs post-transplantation limit further application in clinic practice. To enhance the therapeutic effect of MSC-EVs for kidney diseases, EVs are encapsulated in a collagen matrix [39], matrix metalloproteinase-2-sensitive selfassembling peptide hydrogel [40], and arginine-glycineaspartate (RGD) hydrogel [41] to prolong their retention and therefore induce sustained release. Demonstrably, RGD hydrogels interact with EVs mediating by integrin subunits αv, β3, and β8 [41].…”

“…To enhance the therapeutic effect of MSC-EVs for kidney diseases, EVs are encapsulated in a collagen matrix [39], matrix metalloproteinase-2-sensitive selfassembling peptide hydrogel [40], and arginine-glycineaspartate (RGD) hydrogel [41] to prolong their retention and therefore induce sustained release. Demonstrably, RGD hydrogels interact with EVs mediating by integrin subunits αv, β3, and β8 [41]. Besides slowing the eliminating process of EVs, encapsulation can assist EVs kidney to attenuate kidney injury by pathological damage reduction, promotion of cell proliferation, inhibition of renal cell apoptosis, amplification of autophagic activation, and enhancing of angiogenesis as well as ameliorating fibrosis [39][40][41].…”

Activated mesangial cells induce glomerular endothelial cells proliferation in rat anti‐Thy‐1 nephritis through VEGFA/VEGFR2 and Angpt2/Tie2 pathway

“…Mesangial proliferative glomerulonephritis (MPGN) does not represent a specific glomerulopathy. As a pathological description of a class of glomerular diseases with mesangial hyperplasia, it can occur in primary glomerulonephritis (IgA nephropathy, lupus nephritis, infectious glomerulonephritis, IgM nephropathy, etc) and systemic disease (kidney allograft, diabetes, immune complex deposition, etc) 27,28 . MPGN is one of the major factors of chronic kidney disease which leads to end‐stage renal disease.…”

Chitosan Hydrogel-loaded MSC-derived Extracellular Vesicles Promote Skin Rejuvenation by Ameliorating the Senescence of Dermal Fibroblasts

“…Although we know the bene cial effects of stem cell derived EVs on the skin aging, low retention and stability has remained an obstacle for clinical applications (30,61). More importantly, it is necessary to develop a valid method for EV-based therapeutics.…”