Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury
Abstract
:1. Pathophysiology of AKI and CKD
2. Current Treatments for Kidney Failure
3. Regenerative Properties of Mesenchymal Stem Cells
4. Mesenchymal Stem Cell-Derived Extracellular Vesicles
5. Methodologies of Exosome Isolation
6. Therapeutic Applications of MSC-EVs
6.1. Macular Degeneration
6.2. Cancer
6.3. Alzheimer’s Disease
6.4. Ischaemic Stroke
6.5. ARDS and COVID-19
7. Nephroprotective Role of MSC-EVs in AKI
7.1. Tubular Proliferation and Dedifferentiation
7.2. Inhibition of Apoptosis
7.3. Angiogenesis
7.4. Anti-Oxidation
7.5. Immunomodulation
MSC Source | In Vivo Model | EV Subtype | Dose | Administration | Pathophysiological Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|---|
Bone marrow | Glycerol | EVs | Single: 200 μg | Intravenous | EVs accumulate specifically in injured kidneys | [100] | |
Bone marrow | Glycerol | MVs | Single: 15 μg | Caudal vein | MVs accumulated within lumen of injured tubules ↑ proliferation ↓ apoptosis ↑ tubuloepithelial regeneration | Delivery of HGF, MSP | [101] |
Bone marrow | Glycerol | EVs | Single: 16.5 × 107 or 8.25 × 107 | Intravenous | Pro-regenerative miRNA-enriched EVs are superior to naïve EVs at lower doses ↓ BUN, creatinine ↓ necrosis | Pro-regenerative miRNA: miR-10a, miR-486, miR-127 | [105] |
Bone marrow | Cisplatin | MVs | Multiple: 100 μg, then 50 μg days 2, 6, 10, 14, 18 | Intravenous | ↓ apoptosis, necrosis ↑ proliferation ↓ mortality Did not prevent chronic tubular injury at 3 weeks | ↓ Caspase-1,8, lymphotoxin-α ↑ Bcl-2, Bcl-xL, BIRC8 | [109] |
Bone marrow | Cisplatin | EVs | Single: 150 μg | Intra-arterial kidney | ↓ BUN, creatinine ↓ tubular cast formation ↑ proliferation ↓ inflammation | ↓ IL-6, TNF-α, NF-κB | [107] |
Bone marrow | Cisplatin | EVs | Single: 200 μg/100 g body weight on day 3 | Intraperitoneal | Combined pre-treatment with pulsed focused ultrasound on d2 ↓ BUN, creatinine ↓ tissue damage (KIM-1, NGAL) ↓ inflammation | ↓ HSP70, HSP90 activation of NLRP3 inflammasome ↓ IL-1β, IL-18 | [136] |
Bone marrow | Cisplatin | EVs | Single: 150 μg/100 g body weight on day 3 | Caudal vein | Pulsed focused ultrasound pre-treatment ↓ tissue damage (KIM-1, TIMP-1) ↑ proliferation ↑ angiogenesis ↓ apoptosis ↓ inflammation | ↑ ERK signalling ↑ PI3K/Akt ↑ VEGF, PCNA, survivin ↑ SIRT3, eNOS ↓ Caspase-3, Bax ↓ TNF-α, IL-6, IL-1β | [108] |
Bone marrow | Gentamicin | Exosomes | Multiple: 100 μg | Caudal vein | ↓ apoptosis, necrosis ↑ proliferation ↓ inflammation | Unknown RNA ↓ IL-6, IFN-γ, TNF-α; ↑ IL-10 | [98] |
Bone marrow | IRI | Exosomes | Single: 200 μg | Renal capsule | ↓ macrophage infiltration ↓ inflammation | CCR2 expression on exosomes suppress CCL2 activity | [134] |
Bone marrow | IRI | Exosomes preconditioned with 5 μM melatonin | Single: 250 μg | Perfusion | ↓ BUN, creatinine ↓ apoptosis ↓ oxidative stress ↓ inflammation ↑ regeneration ↑ angiogenesis | Melatonin: ↓ Caspase-3, Bax, PARP1; ↑ Bcl-2 ↓ ROS: MDA, HIF-1α, NOX2 ↑ anti-oxidants (HO-1, SOD, CAT, GPX) ↓ MPO activity, ICAM-1, IL-1β, NF-κB; ↑ IL-10 ↑ bFGF, HGF, Sox9, VEGF | [113] |
Bone marrow | IRI | Exosomes enriched with miR-199a-3p | Single: 5 × 105 | Caudal vein | ↓ apoptosis | ↓ Sema3A and reactivate Akt and ERK pathways ↓ Caspase-3 | [112] |
Bone marrow | IRI | Exosomes enriched with miR-199a-5p | Single: 5 × 105 | Caudal vein | ↓ endoplasmic reticulum stress at 8–16 h after reperfusion ↓ apoptosis | Targets BIP | [123] |
Bone marrow | IRI, nephrectomy | EVs | Single: released from 3 × 106 MSCs | Perfusion | ↓ ischaemic damage | ↑ Expression of proteins in membrane transport and homeostasis (Calb1, Slc16a1, vaculor H+-ATPase d2 subunit) | [74] |
Bone marrow | UUO | EVs | Single: 0.5 mg/kg | Intravenous | ↓ inflammation ↓ macrophage infiltration (ED-1+) ↓ mitochondrial damage ↓ oxidative stress ↓ apoptosis ↓ fibrosis | Delivered MFG-E8 to inhibit RhoA/ROCK pathway ↓ IL-1β, TNF-α, IL-6 ↓ MDA; ↑ anti-oxidants (SOD, CAT) ↓ Caspase-3, PARP1 ↓ α-SMA, ↓fibronectin, ↑E-cadherin | [135] |
Umbilical cord | Cisplatin | Exosomes | Single: 200 μg | Renal capsule | ↓ apoptosis, necrosis ↓ oxidative stress ↑ proliferation | ↓ Caspase 3 ↓ p38 MAPK pathway | [106] |
Umbilical cord | Cisplatin | Exosomes | Single: 200 μg | Renal capsule | ↑ autophagy: ↑LC3B ↓ BUN, creatinine after 3d ↓ apoptosis ↓ inflammation | ↓ mTOR activity ↓ Bax, ↓ Caspase-3; ↑ Bcl-2, Bcl-XL ↓ IL-1β, IL-6, TNF-α | [114] |
Umbilical cord | Cisplatin | Exosomes | Single: 200 μg | Renal capsule | ↑ autophagy ↓ BUN, creatinine after 3d ↓ apoptosis | Delivered 14–3-3ζ to ↑ autophagy via promoting the localisation of ATG16L ↓ Caspase 3 | [115] |
Umbilical cord | IRI | EVs overexpressing Oct4 | Single: 100 μg | Caudal vein | ↓ BUN, creatinine ↓ apoptosis ↑ proliferation ↓ fibrosis | Oct4 inhibited fibrosis (↓ SNAIl, α-SMA) | [117] |
Umbilical cord | Sepsis (caecal ligation and puncture) | Exosomes | Single: 120 μg | Caudal vein | ↓ BUN, creatinine ↓ apoptosis ↓ inflammation ↑ survival (45% vs. 28% control) | Upregulation of miR-146b ↓ IRAK1 and ↓ NF-κB expression ↓ IL-1β, TNF-α | [137] |
Wharton’s jelly | IRI | MVs | Single: 100 μg | Caudal vein | ↓ BUN, creatinine ↓ apoptosis ↑ tubular cell proliferation ↓ inflammation ↓ CD68+ macrophage infiltration ↓ fibrosis | Delivery of miRN-15a/-15b/-16 reduced CX3CL ↓ α-SMA | [110] |
Wharton’s jelly | IRI | MVs | Single: 100 μg | Caudal vein | ↓ oxidative stress ↓ apoptosis ↑ proliferation ↓ fibrosis | ↓ NOX2 expression, ↓ ROS levels ↓ α-SMA | [119] |
Wharton’s jelly | IRI | MVs | Single: 30 μg | Caudal vein | ↑ tubular cell dedifferentiation and growth | ↑ HGF RNA | [103] |
Wharton’s jelly | IRI | MVs | Single: 100 μg | Intravenous | ↑ survival ↓ BUN, creatinine ↓ apoptosis ↑ proliferation ↓ inflammation ↓ CD68+ macrophage infiltration ↓ fibrosis | ↓ TNF-α; ↑ IL-10 ↓ α-SMA, TGF-β1 ↑ HGF | [118] |
Wharton’s jelly | IRI | EVs | Single: 100 μg | Intravenous | ↓ BUN, creatinine after 24 h ↓ NK cells in kidney without the involvement of the spleen | ↓ CX3CL1, TLR2 | [138] |
Wharton’s jelly | IRI | EVs | Single: 100 μg | Caudal vein | ↑ angiogenesis ↓ fibrosis | Delivery of VEGF and its RNA; ↓ HIF-1α, α-SMA | [124] |
Wharton’s jelly | IRI | EVs | Single: 100 μg | Caudal vein | ↓ mitochondrial fission ↓ apoptosis | Delivery of miR-30b/c/d | [120] |
Wharton’s jelly | IRI | EVs | Single: 100 μg | Caudal vein | ↓ oxidative stress↓ renal cell injury (↓NGAL) ↓ apoptosis | ↑ Nrf2/ARE activation ↑ ROS scavenging enzymes (HO-1) | [130] |
Renal | IRI | EVs | Single: 4 × 108 | Intravenous | EVs detected in ischaemic kidneys within 1 h ↓ BUN, creatinine ↑tubular cell proliferation | Identified 62 miRNAs | [53] |
Renal | IRI | EVs | Single: 2 × 107 | Caudal vein | ↓ apoptosis ↑ peritubular capillary endothelial cell proliferation ↑ angiogenesis | Selective engraftment in ischaemic kidneys Delivery of VEGF-A, bFGF, IGF-1 | [111] |
Adipose | IRI | Exosomes | Single: 100 μg | Intravenous | Combined ADMSC and exosome therapy is superior to monotherapy: ↓ proteinuria ↓ kidney injury score | [140] | |
Adipose | Sepsis (caecal ligation and puncture) | Exosomes | Single: 100 μg | Caudal vein | ↓ inflammation ↓ inflammatory cell infiltration ↓ apoptosis ↓ mortality | ↑ SIRT1 inhibited NF-κB and its inflammatory activity ↓ TNF-α, IL-6, MCP-1 ↓ Bax, ↓ Caspase-3; ↑ Bcl-2 | [141] |
Human induced pluripotent stem cells | IRI | EVs | Single: 1 × 1012 | Intravenous | ↓ necroptosis | Delivery of SP1 to renal cells | [122] |
Human placenta-derived | IRI | EVs | Single: 80 μg | Intravenous | EVs specifically accumulated in ischaemic kidney and taken up by proximal TECs ↑ mitochondrial antioxidant defence ↓ mitochondrial fragmentation | Keap1-Nrf2 pathway- ↑ SOD2, ↑ATP production | [132] |
Human placenta-derived | IRI | EVs | Multiple: 100 μg daily for 3 days | EVs travelled to injured kidneys ↑ proliferation and regeneration ↓ BUN, creatinine ↓ apoptosis ↓ fibrosis d28 | ↑ Sox9+ expression in tubular epithelial cells ↓ α-SMA, fibronectin, collagen I, TGF-β1 | [142] |
8. Anti-Fibrotic Effect of MSC-EVs in CKD
8.1. Downregulate Pro-Fibrotic Gene Expression and the EMT
8.2. Reduce Tubular Atrophy
8.3. Vascular Regeneration
8.4. Anti-Inflammatory
MSC Source | In Vivo Model | EV Subtypes | Dose | Administration | Pathophysiological Effects | Mechanism of Action | Ref. |
---|---|---|---|---|---|---|---|
Bone marrow | IRI | MVs | Single: 30 μg | Intravenous | ↓ BUN, creatinine, proteinuria ↓ fibrosis, ↓glomerular matrix accumulation ↓ interstitial lymphocyte infiltrate ↓ tubular atrophy | Dependent on RNA cargo | [104] |
Bone marrow | Chronic CsA | EVs | Multiple: 100 μg Preventive: 24 h after CsA, weekly for 4 weeks Curative: 2 weeks after CsA, weekly for 4 weeks | Intraperitoneal | Greater improvement when administered after damage (curative regime), rather than prophylactically ↓ tubular casts | ↓ PAI-1, TIMP-1, IFN-γ | [154] |
Bone marrow | Aristolochic acid | EVs | Single: 1 × 1010 on day 3 | Intravenous | ↓ BUN, creatinine ↓ necrosis ↓ CD45+ immune cells, fibroblast, pericyte infiltration ↓ interstitial fibrosis | Downregulation of hsa-miR-21-5p, 34a-5p, 34c-5p, 132-3p, 214-3p, 342-3p; and mmu-miR-212-3p Upregulation of hsa-miR-194-5p, 192-5p; and mmu-miR-378-3p ↓ α-SMA, TGF-β1, collagen Iα1 | [151] |
Bone marrow | 5/6 subtotal nephrectomy | MVs | Multiple: 30 μg, days 2, 3, 5 | Caudal vein | ↓ BUN, creatinine, uric acid, proteinuria prevent fibrosis ↓ tubular atrophy ↓ interstitial lymphocyte infiltrate | [153] | |
Bone marrow | UUO | MVs | Single: 30 μg | Caudal vein | ↓ BUN, creatinine ↓ fibrosis | ↓ TGF-β1, α-SMA ↑ E-cadherin | [152] |
Bone marrow | UUO | Exosomes enriched with miR-let7c | Single: released from 1 × 106 MSCs | Intravenous | Exosomes home to injured kidneys ↓ fibrosis | Delivery of miRNA-let7c ↓ collagen, MMP-9, α-SMA, TGF-βR1 | [149] |
Bone marrow | Type 2 diabetes, STZ Type 1 diabetes | Exosomes | Single: 5.3 × 107 | Renal subcapsular | ↓ degeneration, vacuolation and tubular atrophy ↓ EMT ↓ ICAM-1-mediated interstitial inflammatory infiltration | ↓ TGF-β ↓ TNF-α | [16] |
Bone marrow | STZ Type 1 diabetes | Exosomes | Single: 100 μg | Intravenous | ↑ Autophagy: ↑ LC3-II, Beclin-1 ↓ BUN, creatinine, blood glucose, proteinuria at 10 and 12 weeks ↓ fibrosis | ↓ mTOR activity ↓ collagen, TGF-β | [165] |
Bone marrow, Liver | STZ Type 1 diabetes | EVs | Multiple: 1 × 1010 | Intravenous | ↓ BUN, creatinine ↓ fibrosis, ↓ EMT ↓ inflammatory cell recruitment | ↓ collagen I, MMP3, TIMP1, FasL, Serpina1a, SNAI1 ↓ CCL3 | [54] |
Umbilical cord | STZ-induced DN with hyperuricaemia | MVs enriched with miR-451a | Single: 1.5 mg/kg | Caudal vein | ↓ BUN, creatinine ↓ fibrosis, ↓ EMT ↑ proliferation and removed arrest on cell cycle | ↓ α-SMA, ↑ E-cadherin miR-451a targeted 3′UTR sites of cell cycle inhibitors (P15INK4b, P19INK4d) | [150] |
Umbilical cord | UUO | Exosomes | Single: 200 μg | Intravenous | ↓ tubulointerstitial fibrosis | Exosomes delivered casein kinase 1δ and E3 ubiquitin ligase β-TRCP to degrade YAP | [166] |
Umbilical cord | UUO | Exosomes | Single: 200 μg | Intra-arterial kidney | ↓ BUN, creatinine ↓ apoptosis ↓ oxidative stress ↓ tubulointerstitial fibrosis | ↓ ROS-mediated p38 MAPK/ERK signalling pathway ↓ ROS: MDA ↑ anti-oxidants: GSH | [145] |
Wharton’s jelly | CsA | EVs | Multiple: 100 μg at day 7, 21 | Intravenous | ↓ creatinine ↓ fibrosis, ↓ EMT ↓ oxidative stress | ↓ α-SMA ↓ ROS: MDA ↑ anti-oxidants: SOD | [146] |
Renal | UUO | MPs | Single: 2 × 107 | Caudal vein | ↓ EndoMT of PTC endothelial cells ↓ PTC rarefaction ↓ F4/80+ inflammatory cell infiltration ↓ tubulointerstitial fibrosis | ↓ α-SMA | [155] |
Renal | UUO | EPO-enriched MPs | Single: 80 μg | Caudal vein | ↓ tubulointerstitial fibrosis, ↓ EMT ↓ myofibroblast and F4/80+ macrophage infiltration | ↓ phosphorylated Smad2, Smad3, MAPK 38 expression to inhibit EMT ↓ α-SMA, fibronectin, collagen | [144] |
Adipose (transfected with GDNF) | UUO | Exosomes | Single: 200 μg | Caudal vein | ↓ PTC rarefaction ↓ tubulointerstitial fibrosis ↑ endothelial function and angiogenesis | GDNF: ↑ SIRT1/p-eNOS pathway ↓ α-SMA ↑ VEGF, ↓ HIF-1α | [167] |
Adipose | IRI | Exosomes | Single: 100 μg | Caudal vein | ↑ tubular proliferation, regeneration ↓ TGF-β1-induced transformation of TECs to pro-fibrotic phenotype ↓ AKI to CKD transition | ↑ Sox9 ↓ α-SMA, PDGFR-β | [168] |
Adipose | Type 1 diabetes | Exosomes | Single: not stated, 12-week therapy | Caudal vein | ↓ BUN, creatinine, proteinuria ↑ autophagy, ↓ apoptosis podocytes | miR-486 reduced Smad1 expression, leading to ↓ mTOR activation | [169] |
Adipose | Hindlimb Ischaemia | Melatonin-stimulated exosomes | CKD-MSCs treated with 30 μg exosomes, and 1 × 106 cells injected | Injection into ischaemic site | CKD-MSCs were treated with melatonin-stimulated exosomes and injected into mice ↑ neovascularisation ↑ functional recovery | Upregulation of miR-4516 ↑ PrPc in exosomes | [170] |
Adipose | DN (C57BL/KsJ db/db) | EVs | Single | Caudal vein | ↓ histopathology of DN, ↓ BUN, creatinine ↓ VEGFA leads to ↓ podocyte apoptosis | miR-26a-5p inhibited TLR4 and inactivated NF-κB/VEGFA pathway (↓ IKKβ, IκBα, p65) ↓ Caspase-3, Bax, ↑ Bcl-2 | [161] |
Adipose | Unilateral renovascular disease on background of Metabolic Syndrome | EVs | Single: 1 × 107 | Intra-renal vein | ↑ cortical microvascular, PTC density ↑ RBF, GFR ↓ glomerular, tubulointerstitial fibrosis ↓ apoptosis ↓ oxidative stress | Delivered proangiogenic factors: VEGF-A,C, VEGF receptor, angiopoietin like 4, HGF ↓ Caspase-3 ↓ ROS: superoxides, CD31, nitro tyrosine | [158] |
Adipose | Unilateral renal artery stenosis on background of Metabolic Syndrome | EVs | Single: 1 × 1010 | Intrarenal artery | EVs derived from lean pigs were injected into pigs with Metabolic Syndrome | ↑ TGF-β induction of Tregs ↓ IL-1β | [163] |
↑ anti-inflammatory M2 macrophages | |||||||
↓ pro-inflammatory M1 macrophages | |||||||
↓ CD8+ T cells | |||||||
Adipose | Unilateral renal artery stenosis on background of Metabolic Syndrome | EVs | Single: 1 × 1010 | Intrarenal artery | Metabolic Syndrome alters the cargo of 19 mitochondria-related miRNA, impairing regenerative capacity | ↑ miR-196a, 132 ↓ miR-192, 320 | [164] |
Adipose | Unilateral renal artery stenosis | MVs, exosomes | Single: 100 μg | Caudal vein | ↓ HIF-1α Stabilised systolic blood pressure ↓ proteinuria (MVs only) ↑ natriuresis (exosomes only) ↓ fibrosis ↓ inflammation | ↓ collagen I, TGF-β ↑ IL-10 | [147] |
Urine | STZ Type 1 diabetes | Exosomes | Multiple: 100 μg weekly x × 12 | Intravenous | ↓ apoptosis of podocyte and tubular cells ↑ glomerular endothelial cell proliferation ↑ angiogenesis | ↓ Caspase-3 Delivery of VEGF, TGF-β1, angiogenin, BMP7 | [121] |
9. Biological Cargo Carried by MSC-EVs to Alleviate AKI and CKD
9.1. mTOR
9.2. 14-3-3ζ
9.3. YAP
9.4. Oct-4
9.5. SP1
9.6. Sox-9
9.7. SIRT1
9.8. MFG-E8
9.9. Melatonin and PrPc
10. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Method | Differential Ultracentrifugation | Density Gradient | Size Exclusion Chromatography | Invitrogen Precipitation | Affinity-Based |
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Principle | Based on size and sedimentation rate by successive centrifugation at increasing speed and duration [61,62] | Based on density upon flotation or pelleting [45,63] | Based on separating sample molecules relative to pore size of chromatography gel column [57,64] | Compound polymer-based precipitation [63] | Affinity interaction between surface protein, sugar, or lipids, with antibodies coated on magnetic beads [48,57,63,65] |
Yield | Intermediate | Low | Intermediate | High | Low |
Purity | Low | Intermediate | High | Low | Highest |
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Birtwistle, L.; Chen, X.-M.; Pollock, C. Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury. Int. J. Mol. Sci. 2021, 22, 6596. https://doi.org/10.3390/ijms22126596
Birtwistle L, Chen X-M, Pollock C. Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury. International Journal of Molecular Sciences. 2021; 22(12):6596. https://doi.org/10.3390/ijms22126596
Chicago/Turabian StyleBirtwistle, Lucy, Xin-Ming Chen, and Carol Pollock. 2021. "Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury" International Journal of Molecular Sciences 22, no. 12: 6596. https://doi.org/10.3390/ijms22126596