Table 1 Characteristics of included studies
From: Extracellular vesicles for acute kidney injury in preclinical rodent models: a meta-analysis
Study | Country or region | Injury type | Species | Sex | Number | Cell source of EVs | Diameter (nm) | Administration methods | Therapy time | Measurement time | Dose | Main finding |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Wang et al. [18] | China | IRI (45 min, bilateral) | BALB/c mice | Male | C: 5 T: 5 | BMSC | 120.6 (40–150)b | Tail vein | 1 h prior to IRI | 8, 16, 24, and 48 h after reperfusion | 5 × 1010 particles in 100 μL | The 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] | China | CLP | C57BL/6 mice | Male | C: 4 T: 4 | Derived from rIPC mice | 15–150 | Tail vein | After CLP | 24 h | 30 μg | Demonstrated 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] | China | IRI (cardiac arrest induced then transplant) | SD rats | Male | C: 40 T: 40 | WJMSC | NR | Tail vein | After renal transplantation | 24 h, 48 h, 1 and 2 weeks | 100 μg in 1 mL | The administration of MVs immediately after renal transplantation ameliorated IRI in both the acute and chronic stages. |
Vinas et al. [21] | Canada | IRI (30 min, bilateral) | FVB mice | Male | C: 6 T: 4 | UVEC | 88 | Tail vein | After reperfusion | 24 h | 20 μg in 100 μL | UVEC 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] | USA | IRI (50 min, bilateral) | Nude rats | NR | C: 4 T: 5 | Human renal tubular cells | 115 ± 0.9a | Tail vein | 2 days after reperfusion | 1–6 days | 100 μg | Renal 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] | China | IRI (45 min on left kidney, remove right kidney) | SD rats | Male | C: 6 T: 6 | Ischaemic preconditioned kidney serum | 225 ± 83.2a (150–350) | Intravenous | After reperfusion | 24 h | 100 μg | Remote ischaemic preconditioning played a therapeutic role in renal IRI through EVs induced by hypoxia. |
Wang et al. [24] | China | Cisplatin (5 mg/kg, 3 days) | SD rats | NR | C: 6 T: 6 | UCMSC | Peaking at 102 | Renal capsule | 0.5 h before cisplatin administration | 24 h, 48 h, 72 h | 200 μg | UCMSC-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] | Italy | IRI (35 min on left kidney, remove right kidney) | SCID mice | Male | C: 6 T: 6 | Gl-MSC-EVs | 170 ± 62a | Tail vein | After reperfusion | 48 h | 4 × 108 particles | Gl-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] | USA | IRI (50 min, bilateral) | SD rats | Female | C: 5 T: 5 | Renal tubular cells | 100 ± 3.94a | Tail vein | 24 h and 48 h | 1–6 days | 100 μg in 0.5 mL | Treatment with EVs from adult renal cells applied well after IRI improved multiple structure and function parameters and transcriptome profiles. |
Bruno et al. [27] | Italy | Glycerol (8 mL/kg, 3 days) | SCID mice | NR | C: 10 T: 10 | BMSC | 160 ± 72a | Tail vein | 3 days after glycerol injection | 48 h | 165 × 106 particles | The different molecular compositions of exosome- and microvesicle-enriched populations may explain the regenerative effect of EVs observed in AKI. |
Zou et al. [28] | China | IRI (45 min on left kidney, remove right kidney) | SD rats | Male | C: 12 T: 12 | UCMSC | 211.4 ± 61.7a (150–350) | Tail vein | After reperfusion | 24 h | 100 μg in 0.5 mL | MSC-EVs ameliorated renal ischaemic reperfusion injury by decreasing NK cells, and the spleen was not necessary in this process. |
Zou et al. [29] | China | IRI (45 min on left kidney, remove right kidney) | Rats | Male | C: 18 T: 18 | UCMSC | 211.4 ± 61.7a (150–350) | Tail vein | After reperfusion | 24 h | 100 μg in 1 mL | Human 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] | China | IRI (45 min on left kidney, remove right kidney) | Rats | Male | C: 6 T: 6 | WJMSC | 30–500 | Tail vein | After reperfusion | 24 h | 100 μg in 1 mL | MSC-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] | Canada | IRI (30 min, bilateral) | FVB mice | Male | C: 5 T: 7 | UVEC | 91 (40–100)b | Jugular vein | After reperfusion | 24 h | 20 μg | The delivery of UVEC exosomes reduced ischaemic kidney injury via the transfer of mir-486-5p targeting PTEN. |
Shen et al. [32] | China | IRI (60 min, left kidney) | BALB/c mice | NR | C: 3 T: 3 | BMSC | NR | Renal capsule | 10 min after reperfusion | 24 h | 200 μg in 20 μL | CCR2 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] | Taiwan | IRI (bilateral) | SD rats | Male | C: 8 T: 8 | ADMSC | NR | Intravenous | 3 h after reperfusion | 72 h | 100 μg | Combined exosome-ADMSC therapy was superior to either one alone for protecting the kidney from acute IRI. |
Gu et al. [34] | China | IRI (45 min on left kidney, remove right kidney) | SD rats | Male | C: 6 T: 6 | WJMSC | NR | Tail vein | After reperfusion | 24 h | 100 μg in 1 mL | Single administration of WJMSC-EVs protected the kidney from IRI by inhibiting mitochondrial fission via mir-30. |
de Almeida et al. [35] | Brazil | Cisplatin (15 mg/kg) | C57BL/6 mice | NR | C: 8 T: 8 | Adult male mice inguinal adipose tissue | 125 | Intravenous | 24 h after cisplatin administration | 0, 24 h, 48 h, 72 h, 96 h | 100 μg | MSCs 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] | China | IRI (60 min, left kidney) | SD rats | Male | C: 24 T: 24 | UCMSC | 142 (80–1000)b | Tail vein | After reperfusion | 24 h, 48 h, 1 week, or 2 weeks | 30 μg in 0.5 mL | MV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitated cell dedifferentiation and growth, which are important regenerative mechanisms. |
Burger et al. [37] | Canada | IRI (30 min, bilateral) | NOD-SCID mice | NR | C: 6 T: 7 | UVEC | EV: 86 (40–100)b MP: 223 (100–1000)b | Jugular vein | After reperfusion | 24 h and 72 h | EVs: 15 μg UVECs: 106 in 100 μL | UVEC-derived exosomes may mediate the protective response by inhibiting endothelial cell apoptosis. |
Zou et al. [38] | China | IRI (60 min, left ischaemia, remove right kidney on day 12) | SD rats | Male | C: 18 T: 18 | WJMSC | 30–500 | Tail vein | After reperfusion | 24 h, 48 h, 2 weeks | 100 μg in 1 mL | Single 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] | China | IRI (60 min on left kidney, remove right kidney on day 12) | SD rats | Male | C: 6 T: 6 | WJMSC | 30–500 | Tail vein | After reperfusion | 24 h, 48 h, 2 weeks | 100 μg in 1 mL | Single 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] | China | IRI (45 min on left kidney, remove right kidney) | SD rats | Male | C: 6 T: 6 | BMSC | 30–60 | Carotid artery | After reperfusion | 48 h | 100 μg | Rat BMSC-derived exosomes protected against IRI, with a decreased inflammatory response and apoptosis in rats. |
Herrera Sanchez et al. [41] | Italy | Glycerol (8 mL/kg, 3 days) | SCID mice | NR | C: 18 T: 9 | HLSC | 174 ± 64 | Tail vein | 3 days after glycerol injection | Day 5 after glycerol administration | EVs produced by 3.5 × 105 HLSCs | HLSCs increased recovery after AKI. EVs were the main component of HLSC-derived CM capable of promoting regeneration in experimental AKI. |
Choi et al. [42] | Korea | IRI (30 min, bilateral) | FVB/N mice | Male | C: 5 T: 5 | KMSC | NR | Tail vein | After reperfusion | 0, 24 h, 72 h | 2 × 107 in 150 μL | KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischaemic kidneys. |
Zhou et al. [43] | China | Cisplatin (6 mg/kg) | SD rats | Female | C: 6 T: 6 | UCMSC | 40–100 | Renal capsule | 24 h after cisplatin administration | 1–5 days | 200 μg | UCMSC-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] | Finland | IRI (40 min, bilateral) | SD rats | Male | C: 8 T: 5 | UCMSC | The smallest being around 20 nm and the largest > 500 nm | Left carotid artery | After reperfusion | 0, 24 h, 48 h | NR | Inflammatory conditioning of MSCs influenced the protein content and functional properties of MVs, revealing the complexity of MSC paracrine regulation. |
Cantaluppi et al. [45] | Italy | IRI (45 min on left kidney, remove right kidney) | Wistar rats | Male | C: 6 T: 6 | EPCs were isolated from peripheral blood mononuclear cells | 60–160 | Tail vein | After reperfusion | 48 h | 30 μg | MVs 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] | Italy | Cisplatin (12 mg/kg) | SCID mice | Male | C: 8 T: 8 | BMSC | 135 (80–1000)b | Tail vein | 8 h after cisplatin administration; 10, 14, and 18 after cisplatin | 24 h | 100 μg | MVs 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] | Italy | IRI (45 min on left kidney, remove right kidney) | SD rats | Male | C: 6 T: 6 | BMSC | 135 (80–1000)b | Intravenous | After reperfusion | 48 h | 30 μg | MVs released from MSCs protected from AKI induced by ischaemia reperfusion injury and from subsequent chronic renal damage. |
Bruno et al. [48] | Italy | Glycerol (8 mL/kg, 3 days) | SCID mice | Male | C:6 T: 6 | BMSC | 180 | Tail vein | 3 days after glycerol injection | 3 days, 5 days, 8 days, 15 days | 15 μg | MVs derived from MSCs activated a proliferative programme in surviving tubular cells after injury via a horizontal transfer of mRNA. |