Extracellular vesicles for acute kidney injury in preclinical rodent models: a meta-analysis

Abstract

IntroductionExtracellular vesicles (EVs), especially stem cell-derived EVs, have emerged as a potential novel therapy for acute kidney injury (AKI). However, their effects remain incompletely understood. Therefore, we performed this meta-analysis to systematically review the efficacy of EVs on AKI in preclinical rodent models.MethodsWe searched PubMed, EMBASE, and the Web of Science up to March 2019 to identify studies that reported the treatment effects of EVs in a rodent AKI model. The primary outcome was serum creatinine (Scr) levels. The secondary outcomes were the blood urea nitrogen (BUN) levels, renal injury score, percentage of apoptotic cells, and interleukin (IL)-10 and tumour necrosis factor (TNF)-α levels. Two authors independently screened articles based on the inclusion and exclusion criteria. The meta-analysis was conducted using RevMan 5.3 and R software.ResultsThirty-one studies (n = 552) satisfied the inclusion criteria. Pooled analyses demonstrated that the levels of Scr (SMD = − 3.71; 95% CI = − 4.32, − 3.10; P < 0.01), BUN (SMD = − 3.68; 95% CI = − 4.42, − 2.94; P < 0.01), and TNF-α (SMD = − 2.65; 95% CI = − 4.98, − 0.32; P < 0.01); the percentage of apoptotic cells (SMD = − 6.25; 95% CI = − 8.10, − 4.39; P < 0.01); and the injury score (SMD = − 3.90; 95% CI = − 5.26, − 2.53; P < 0.01) were significantly decreased in the EV group, and the level of IL-10 (SMD = 2.10; 95% CI = 1.18, 3.02; P < 0.01) was significantly increased. Meanwhile, no significant difference was found between stem cell-derived EVs and stem cells.ConclusionThe present meta-analysis confirmed that EV therapy could improve renal function and the inflammatory response status and reduce cell apoptosis in a preclinical rodent AKI model. This provides important clues for human clinical trials on EVs.

Reproducible Large-Scale Isolation of Exosomes from Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Application in Acute Kidney Injury

“…It is now widely accepted that MSC-exosomes are the next-generation of regenerative therapeutics capable of targeting multiple pathways with regenerative function and overcoming the limitations of cell-based therapeutics [14,53,54]. Several studies have already demonstrated the therapeutic effects of MSC-exosomes from different cell sources, including bone marrow, Wharton's Jelly, and umbilical cords, in a diversity of AKI animal models [7][8][9]. For instance, injection of human umbilical cord-MSC (UC-MSC)-derived exosomes reduced apoptosis and necrosis of proximal kidney tubules by ameliorating oxidative stress in a cisplatin-induced rat AKI model.…”

“…As observed in other disease models, various miRNA cargoes, such as miR-30, miR-199a-5p, miR-486-5p in MSC-exosomes also contribute to the protective and renal-regenerative effects in AKI models as well [58][59][60]. However, the clinical translation of these studies is limited by available exosome-isolation methods; ultracentrifugation-based isolation methods were applied in all of the 31 reported studies on preclinical rodent models [9]. Ultracentrifugation is the most widely used method for isolating exosomes from the MSC-CM [61].…”

“…Mesenchymal stem/stromal cells (MSCs) have been applied to reduce the damage caused by renal injuries in preclinical studies [7]. In addition, mounting evidence has demonstrated that exosomes derived from various MSCs (MSC-exosomes) isolated from different tissue sources, such as bone marrow, adipose tissue, umbilical cord tissue, and umbilical cord blood, have therapeutic potential against kidney diseases including AKI and chronic kidney disease (CKD), in multiple animal models [7][8][9]. Exosomes are nano-sized, lipid-bilayered extracellular vesicles (EVs) that are shed by the fusion of multivesicular bodies (MVBs) with the plasma membrane, and they mediate mainly the paracrine effects of stem-cell therapy [10,11].…”

“…Exosomes are nano-sized, lipid-bilayered extracellular vesicles (EVs) that are shed by the fusion of multivesicular bodies (MVBs) with the plasma membrane, and they mediate mainly the paracrine effects of stem-cell therapy [10,11]. Interestingly, most of the animal studies into the therapeutic effects of MSC-exosomes in kidney injuries have been performed with exosomes isolated almost exclusively by ultracentrifugation [8,9]. The limitations of ultracentrifugation for exosome isolation include the production of exosomes with co-precipitated contaminants such as protein aggregates, the loss of exosome function because of their aggregation or distortion during the isolation process, and functional inhibition of exosomes by the media used in density gradient ultracentrifugation [12].…”

Effects of mesenchymal stromal cell-conditioned media on measures of lung structure and function: a systematic review and meta-analysis of preclinical studies

“…Preclinical studies reiterate the ability MSCs have on dampening lung inflammation. This capacity is largely due to the paracrine secretion of MSC factors (microvesicles, exosomes) that provide a basis for future cell-free therapies for human disease [28][29][30][31]. This is the first review to directly compare the effects of CdM vs MSCs on lung structure and function in animal models of diverse lung disease.…”