Enhanced Therapeutic Effects Of MSC-Derived Extracellular Vesicles With An Injectable Collagen Matrix For Acute Kidney Injury Treatment

Acute kidney injury(AKI)is a syndrome characterized by the rapid loss in renal excretory function,which has the risk of developing into chronic kidney disease(CKD)and ultimately leading to renal failure.Nevertheless,the kidney has relatively limited regenerative ability compared to other organs,such as the liver.Therefore,it is crucial for AKI therapy to regenerate the damaged kidney tissue and delay the progression of CKD to end stage renal disease(ESRD).Mesenchymal stem cell(MSC)-derived extracellular vesicles(EVs)have been shown to have therapeutic potential for ischemic diseases and are considered an alternative to cell therapy.The use of EVs in ischemiareperfusion(IR)-induced acute kidney injury(AKI)has also received increasing attention.However,low retention and poor stability of EVs post-transplantation in vivo remain big obstacles prior to the clinical application of MSC-derived EVs.Therefore,we introduced a collagen matrix gel with biodegradability and biocompatibility.It has lots of biological activities,not only tissue support,but also an important component of extracellular matrix(ECM).When injected into the body,collagen could provide the niche that mimics the natural ECM to better exert the therapeutic effect.Collagen matrix also has a typical three-dimensional(3-D)crosslinking network with high drug/cell embedding rates and local maintenance of drugs/cells.This study was designed to investigate whether human placental MSC-derived EVs(h P-MSC-EVs)encapsulated in collagen matrix(Col-EVs)could increase the retention and stability of EVs and further improve the therapeutic effects of them,leading to a rescued renal function in murine acute kidney injury(AKI)model.In this study,we injected collagen matrix gel and collagen matrix gel-encapsulated EVs into kidney cortex in situ,and then evaluated the therapeutic effect by a series of experiments.The results showed that collagen matrix could effectively encapsulate EVs,significantly improve the stability of EVs,and promote the sustained release of EVs.Moreover,our data revealed that collagen matrix has improved the retention of EVs in the AKI model,which was proved by Gaussia luciferase(Gluc)imaging.The application of collagen matrix remarkably facilitated the proliferation of renal tubular epithelial cells in AKI compared with EVs alone.In addition,collagen matrixincorporated EVs can promote angiogenesis,reduce fibrosis and apoptosis,and restore renal function.Besides,we briefly explored the underlying mechanism of EVs therapy for AKI.We found that EVs play a therapeutic role by inhibiting endoplasmic reticulum(ER)stress.The strategy used in this study provides a practical and effective method to harness EVs for tissue regeneration after AKI.