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Table 1 Characteristics of included studies

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

StudyCountry or regionInjury typeSpeciesSexNumberCell source of EVsDiameter (nm)Administration methodsTherapy timeMeasurement timeDoseMain finding
Wang et al. [18]ChinaIRI (45 min, bilateral)BALB/c miceMaleC: 5
T: 5
BMSC120.6 (40–150)bTail vein1 h prior to IRI8, 16, 24, and 48 h after reperfusion5 × 1010 particles in 100 μLThe administration of BMSC exosomes at the very early reperfusion stages significantly protected against renal I/R injury, and ER stress was closely linked to this protection.
Pan et al. [19]ChinaCLPC57BL/6 miceMaleC: 4
T: 4
Derived from rIPC mice15–150Tail veinAfter CLP24 h30 μgDemonstrated a critical role for exosomal mir-21 in renoprotection conferred by limb rIPC against sepsis and suggested that rIPC and exosomes might serve as possible therapeutic strategies for sepsis-induced kidney injury.
Wu et al. [20]ChinaIRI (cardiac arrest induced then transplant)SD ratsMaleC: 40
T: 40
WJMSCNRTail veinAfter renal transplantation24 h, 48 h, 1 and 2 weeks100 μg in 1 mLThe administration of MVs immediately after renal transplantation ameliorated IRI in both the acute and chronic stages.
Vinas et al. [21]CanadaIRI (30 min, bilateral)FVB miceMaleC: 6
T: 4
UVEC88Tail veinAfter reperfusion24 h20 μg in 100 μLUVEC exosomes selectively targeted the kidneys after ischaemic injury, with rapid cellular transfer of mir-486-5p. Targeting exosomes may involve the interaction between CXCR4 and endothelial cell SDF-1α.
Dominguez et al. [22]USAIRI (50 min, bilateral)Nude ratsNRC: 4
T: 5
Human renal tubular cells115 ± 0.9aTail vein2 days after reperfusion1–6 days100 μgRenal damage from severe ischaemia was broad, and human renal exosomes prevented most protein alterations. Exosomes seem to acutely correct a critical and consequential abnormality during reperfusion.
Zhang et al. [23]ChinaIRI (45 min on left kidney, remove right kidney)SD ratsMaleC: 6
T: 6
Ischaemic preconditioned kidney serum225 ± 83.2a (150–350)IntravenousAfter reperfusion24 h100 μgRemote ischaemic preconditioning played a therapeutic role in renal IRI through EVs induced by hypoxia.
Wang et al. [24]ChinaCisplatin (5 mg/kg, 3 days)SD ratsNRC: 6
T: 6
UCMSCPeaking at 102Renal capsule0.5 h before cisplatin administration24 h, 48 h, 72 h200 μgUCMSC-derived exosomes prevented against cisplatin-induced AKI through an autophagy-related mechanism. Therefore, pretreatment with UCMSC-Ex may be a new method to improve the therapeutic effect of cisplatin.
Ranghino et al. [25]ItalyIRI (35 min on left kidney, remove right kidney)SCID miceMaleC: 6
T: 6
Gl-MSC-EVs170 ± 62aTail veinAfter reperfusion48 h4 × 108 particlesGl-MSCs might contribute to kidney repair after ischaemic AKI. The mechanism can, at least in part, be ascribed to the release of EVs that are able to mimic the effect of Gl-MSCs.
Dominguez et al. [26]USAIRI (50 min, bilateral)SD ratsFemaleC: 5
T: 5
Renal tubular cells100 ± 3.94aTail vein24 h and 48 h1–6 days100 μg in 0.5 mLTreatment with EVs from adult renal cells applied well after IRI improved multiple structure and function parameters and transcriptome profiles.
Bruno et al. [27]ItalyGlycerol (8 mL/kg, 3 days)SCID miceNRC: 10
T: 10
BMSC160 ± 72aTail vein3 days after glycerol injection48 h165 × 106 particlesThe different molecular compositions of exosome- and microvesicle-enriched populations may explain the regenerative effect of EVs observed in AKI.
Zou et al. [28]ChinaIRI (45 min on left kidney, remove right kidney)SD ratsMaleC: 12
T: 12
UCMSC211.4 ± 61.7a (150–350)Tail veinAfter reperfusion24 h100 μg in 0.5 mLMSC-EVs ameliorated renal ischaemic reperfusion injury by decreasing NK cells, and the spleen was not necessary in this process.
Zou et al. [29]ChinaIRI (45 min on left kidney, remove right kidney)RatsMaleC: 18
T: 18
UCMSC211.4 ± 61.7a (150–350)Tail veinAfter reperfusion24 h100 μg in 1 mLHuman MSC-EVs protected against IRI-induced kidney injury through proangiogenesis effects in a HIF-1α-independent manner, and both the delivery of proangiogenesis-related VEGF and RNAs were involved in this process.
Zhang et al. [30]ChinaIRI (45 min on left kidney, remove right kidney)RatsMaleC: 6
T: 6
WJMSC30–500Tail veinAfter reperfusion24 h100 μg in 1 mLMSC-EVs recovered AKI induced by IRI and helped balance oxidative stress/antioxidative responses to favourable levels by enhancing Nrf2/ARE activation.
Vinas et al. [31]CanadaIRI (30 min, bilateral)FVB miceMaleC: 5
T: 7
UVEC91 (40–100)bJugular veinAfter reperfusion24 h20 μgThe delivery of UVEC exosomes reduced ischaemic kidney injury via the transfer of mir-486-5p targeting PTEN.
Shen et al. [32]ChinaIRI (60 min, left kidney)BALB/c miceNRC: 3
T: 3
BMSCNRRenal capsule10 min after reperfusion24 h200 μg in 20 μLCCR2 expressed on MSC-exo may play a key role in inflammation regulation and renal injury repair by acting as a decoy to suppress CCL2 activity.
Lin et al. [33]TaiwanIRI (bilateral)SD ratsMaleC: 8
T: 8
ADMSCNRIntravenous3 h after reperfusion72 h100 μgCombined exosome-ADMSC therapy was superior to either one alone for protecting the kidney from acute IRI.
Gu et al. [34]ChinaIRI (45 min on left kidney, remove right kidney)SD ratsMaleC: 6
T: 6
WJMSCNRTail veinAfter reperfusion24 h100 μg in 1 mLSingle administration of WJMSC-EVs protected the kidney from IRI by inhibiting mitochondrial fission via mir-30.
de Almeida et al. [35]BrazilCisplatin (15 mg/kg)C57BL/6 miceNRC: 8
T: 8
Adult male mice inguinal adipose tissue125Intravenous24 h after cisplatin administration0, 24 h, 48 h, 72 h, 96 h100 μgMSCs regulated a particular miRNA subset of which mRNA targets were associated with the Wnt/TGF-β, fibrosis, and epithelial-mesenchymal transition signalling pathways. MSCs released MVs that transcriptionally reprogram injured cells, thereby modulating a specific miRNA-mRNA network.
Ju et al. [36]ChinaIRI (60 min, left kidney)SD ratsMaleC: 24
T: 24
UCMSC142 (80–1000)bTail veinAfter reperfusion24 h, 48 h, 1 week, or 2 weeks30 μg in 0.5 mLMV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitated cell dedifferentiation and growth, which are important regenerative mechanisms.
Burger et al. [37]CanadaIRI (30 min, bilateral)NOD-SCID miceNRC: 6
T: 7
UVECEV: 86 (40–100)b
MP: 223 (100–1000)b
Jugular veinAfter reperfusion24 h and 72 hEVs: 15 μg
UVECs: 106 in 100 μL
UVEC-derived exosomes may mediate the protective response by inhibiting endothelial cell apoptosis.
Zou et al. [38]ChinaIRI (60 min, left ischaemia, remove right kidney on day 12)SD ratsMaleC: 18
T: 18
WJMSC30–500Tail veinAfter reperfusion24 h, 48 h, 2 weeks100 μg in 1 mLSingle administration of MVs immediately after ischaemic AKI ameliorated renal injury in both the acute and chronic stages, and the anti-inflammatory property of MVs through the suppression of CX3CL1 may be a potential mechanism.
Zhang et al. [39]ChinaIRI (60 min on left kidney, remove right kidney on day 12)SD ratsMaleC: 6
T: 6
WJMSC30–500Tail veinAfter reperfusion24 h, 48 h, 2 weeks100 μg in 1 mLSingle administration of WJMSC-MVs might protect the kidney by alleviating oxidative stress in the early stage of kidney IRI by suppressing NOX2 expression. Moreover, it reduced fibrosis and improved renal function.
Wang et al. [40]ChinaIRI (45 min on left kidney, remove right kidney)SD ratsMaleC: 6
T: 6
BMSC30–60Carotid arteryAfter reperfusion48 h100 μgRat BMSC-derived exosomes protected against IRI, with a decreased inflammatory response and apoptosis in rats.
Herrera Sanchez et al. [41]ItalyGlycerol (8 mL/kg, 3 days)SCID miceNRC: 18
T: 9
HLSC174 ± 64Tail vein3 days after glycerol injectionDay 5 after glycerol administrationEVs produced by 3.5 × 105 HLSCsHLSCs increased recovery after AKI. EVs were the main component of HLSC-derived CM capable of promoting regeneration in experimental AKI.
Choi et al. [42]KoreaIRI (30 min, bilateral)FVB/N miceMaleC: 5
T: 5
KMSCNRTail veinAfter reperfusion0, 24 h, 72 h2 × 107 in 150 μLKMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischaemic kidneys.
Zhou et al. [43]ChinaCisplatin (6 mg/kg)SD ratsFemaleC: 6
T: 6
UCMSC40–100Renal capsule24 h after cisplatin administration1–5 days200 μgUCMSC-ex repaired cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro.
Kilpinen et al. [44]FinlandIRI (40 min, bilateral)SD ratsMaleC: 8
T: 5
UCMSCThe smallest being around 20 nm and the largest > 500 nmLeft carotid arteryAfter reperfusion0, 24 h, 48 hNRInflammatory conditioning of MSCs influenced the protein content and functional properties of MVs, revealing the complexity of MSC paracrine regulation.
Cantaluppi et al. [45]ItalyIRI (45 min on left kidney, remove right kidney)Wistar ratsMaleC: 6
T: 6
EPCs were isolated from peripheral blood mononuclear cells60–160Tail veinAfter reperfusion48 h30 μgMVs derived from endothelial progenitor cells protected the kidney from ischaemic acute injury by delivering their RNA content, the miRNA cargo of which contributes to reprogramming hypoxic resident renal cells to a regenerative programme.
Bruno et al. [46]ItalyCisplatin (12 mg/kg)SCID miceMaleC: 8
T: 8
BMSC135 (80–1000)bTail vein8 h after cisplatin administration; 10, 14, and 18 after cisplatin24 h100 μgMVs released from MSCs were found to exert a prosurvival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs by exerting a prosurvival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection.
Gatti et al. [47]ItalyIRI (45 min on left kidney, remove right kidney)SD ratsMaleC: 6
T: 6
BMSC135 (80–1000)bIntravenousAfter reperfusion48 h30 μgMVs released from MSCs protected from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage.
Bruno et al. [48]ItalyGlycerol (8 mL/kg, 3 days)SCID miceMaleC:6
T: 6
BMSC180Tail vein3 days after glycerol injection3 days, 5 days, 8 days, 15 days15 μgMVs derived from MSCs activated a proliferative programme in surviving tubular cells after injury via a horizontal transfer of mRNA.
  1. Abbreviations: ADMSC adipose derived mesenchymal stromal cells, AKI acute kidney injury, BMSC bone marrow mesenchymal stromal cells, C control group, CLP caecal ligation and puncture, CM conditioned medium, EPC endothelial progenitor cell, EVs extracellular vesicles, Gl-MSC glomerular mesenchymal stromal cells, HLSC human liver stem cells, IRI ischaemia-reperfusion injury, KMSC kidney-derived mesenchymal stromal cells, MP microparticle, MVs microvesicles, rIPC remote ischaemic preconditioning, NR not reported, SD Sprague-Dawley, T treatment group, UCMSC umbilical cord mesenchymal stromal cells, UVEC umbilical vein endothelial cells, WJMSC Wharton’s jelly mesenchymal stromal cells
  2. aMean ± standard error
  3. bMedian (interquartile range)