Systematic review of extracellular vesicle-based treatments for lung injury: are EVs a potential therapy for COVID-19?

Figures & data

Figure 1. Restorative effects of extracellular vesicle (EV) therapies in acute respiratory distress syndrome (ARDS). Compared to the normal alveolus (A), ARDS (B) is characterized by increased pulmonary inflammation [1], increased immune cell recruitment including neutrophils and macrophages [2], increased alveolar epithelial cell apoptosis [3], inactivated surfactant from degradation of alveolar surfactant layer and alveolar wall collapse [4], as well as increased endothelial cell permeability and gap junction formation [5], fibrin deposition [6] and increased platelet formation. EV treatments (C) can ameliorate the majority of these ARDS features by resolving inflammation and angiogenesis [1], altering local immune cell recruitment [2], decreasing apoptosis in alveolar epithelial cells [3], stimulating surfactant proteins leading to re-expansion of the alveolus [4], restoring endothelial junction proteins and decreasing endothelial barrier permeability [5], and reducing fibrin levels [6].

Table 1. Inclusion criteria of the systematic review.

Publication
Language	English
Time period	January 1950 – April 2020
Subject	All species
Study type	Randomized Controlled Trial Prospective Case-control Cohort Retrospective
Excluded	Case-reports Opinion articles Editorials Letters Grey Literature
Keywords	Exosomes Extracellular vesicles Lung Respiratory Pulmonary

Figure 2. Diagram of workflow in the systematic review according to the PRISMA statement.

Table 2. Articles reporting the effects of EV therapy on lung injury models.

Study	Source of EVs	Model	Sample	EV effects	EV treatment outcome summary
Wang et al. 2020 [31]	Adipose MSCs	ALI: in vivo mouse (LPS)	Lung tissue BAL	↓TNF-α, ↓IL-1β, ↓IL-6, ↑IL-10, ↓iNOS, ↓NF-κB	Reduction of inflammation (decreased pro-inflammatory cytokines, increased anti-inflammatory cytokines, and reduced neutrophils in alveolar fluid), pulmonary endothelial barrier permeability, and alveolar septal thickness
		ALI: in vitro mouse BMDMs (LPS)	BMDMs	↓TNF-α, ↓IL-1β, ↓iNOS, ↑YM-1, ↑MRC-1, ↑miR-27a-3p
Dinh et al. 2020 [32]	Lung spheroid cells	Fibrosis: in vivo mouse (BLM)	Lung tissue	↑AQP5, ↑vWF, ↓αSMA, ↓SMAD3, ↓Hydroxyproline	Promotion of alveolar repair (increased aquaporin), attenuation of vascular injury and reduction of collagen deposition
Gao et al. 2020 [33]	Adipose MSCs	ALI: in vivo rat (PM2.5)	Lung tissue BAL	↓TNF-α, ↓ROS	Reduction of inflammation (decreased pro-inflammatory cytokines and oxidative stress), alveolar epithelial apoptosis and necrosis, and alveolar wall oedema and collapse
		ALI: in vitro rat AEC2 (PM2.5)	AEC2	↓Apoptosis
Yu et al. 2020 [34]	Adipose tissue, Adipose MSCs, Serum	ALI: in vivo mouse (Ventilator-induced lung injury)	Lung tissue BAL	↓IL-6, ↓TRPV4, ↑β-Catenin, ↑VE-Cadherin ↓MPO	Reduction of inflammation (decreased pro-inflammatory cytokines) and pulmonary endothelial barrier permeability
		ALI: in vitro PMVECs (Cyclic stretching)	PMVECs	↓TNF-α, ↓IL-6, ↓TRPV4, ↑β-Catenin, ↑VE-Cadherin
Huang et al. 2019 [35]	Adipose MSCs	ALI: in vivo mouse (LPS)	Lung tissue BAL	↓IL-1β and ↑IL-10	Reduction of inflammation (lower neutrophil and macrophage recruitment in alveolar fluid) and alveolar wall thickness
		ALI: in vitro mouse BMDMs (LPS)	BMDMs	↓IL-6, ↓IL-1β, ↓TNF-α, ↓iNOS, ↑TGF-β1, ↑YM-1
Silva et al. 2019 [36]	Bone marrow MSCs	ARDS: in vivo mouse (LPS)	Lung tissue	↓TNF-α, ↓IL-6, ↓KC, ↓VEGF, ↓TGF- β	Reduction of inflammation (lower neutrophils and macrophages in alveolar fluid) and alveolar wall collapse
		ARDS: in vitro mouse alveolar macrophages (LPS)	Serum	↓iNOS, ↓IL-1β, ↓IL-6, ↑Arginase, ↑TGF-β
Zhang et al. 2019 [37]	PMVECs with high levels of Syndecan-1 (SDC1)	ALI: in vivo mouse (LPS)	Lung tissue	↓IL-6, ↓IL-1β, ↓TNF-α	Reduction of inflammation (decreased pro-inflammatory cytokines), preservation of pulmonary endothelial function, and decrease in alveolar wall thickness
		ALI: in vitro mouse PMVECs (LPS)	PMVECs	↓F-actin, ↓MLC, ↓MYPT1, ↓NF-κB
Hao et al. 2019 [38]	Bone marrow MSCs	ALI: in vivo mouse (E. coli)	BAL	↓MIP-2, ↓TNF-α, ↑LTB4	Antimicrobial effect (increased monocyte phagocytosis and decreased bacterial levels) and reduction of inflammation (decreased leukocytes and neutrophils in alveolar fluid)
		ALI: in vitro mouse RAW267.4 cells (LPS)	RAW267.4	↓MRP1-protein, ↑miR-145
Kim et al. 2019 [39]	Placental chorionic and decidual MSCs	ALI: in vitro human BEAS-2B and THP-1 cells (LPS)	THP-1 BEAS-2B	↓TNF-α	Reduction of inflammation (decreased oxidative stress and pro-inflammatory cytokines) and restoration of bronchiolar epithelial cell migration and proliferation
Yi et al. 2019 [40]	Bone marrow MSCs	ALI: in vivo mouse (LPS)	Lung tissue	↓MPO, ↓IL-1β, ↓TNF-α, ↓IL-6, ↑KGF, ↑IL-10, ↓SAA3	Reduction of inflammation (decreased pro-inflammatory cytokines), alveolar epithelial apoptosis, and lung interstitial vessel and alveolar septal thickness
		ALI: in vitro mouse AEC2 (LPS)	BAL AEC2	↓SAA3, ↓NF-κB, ↓ERK1/2, ↓p38MAPK, ↓MEK1/2, ↓JNK, ↑miR-30b-3p
Chen et al. 2019 [41]	Umbilical cord MSCs	ALI: in vivo rat (BLM)	Lung tissue BAL	↓TNF-α, ↓IL-6, ↑HGF, ↑c-Met, ↑Akt, ↑mTOR	Reduction of inflammation (reduced leukocytes and neutrophils in alveolar fluid and pro-inflammatory cytokines), alveolar epithelial apoptosis, alveolar wall thickness, pulmonary hyaline membrane, and collagen deposition
		ALI: in vitro rat AEC2 and rat PMVECs (BLM)	AEC2 PMVECs	↑c-Met, ↑Akt, ↑mTOR, ↑HGF
Xu et al. 2019 [42]	Bone marrow MSCs	ALI: in vivo rat (Phosgene-induced)	Lung tissue BAL Plasma	↓MMP-9 ↑SP-C ↓TNF-α, ↓IL-1β, ↓IL-6, ↑IL- 10	Restoration of respiratory function (increased peak of inspiratory and expiratory flow, decreased lung resistance), reduction of inflammation (decreased oedema, pro-inflammatory cytokines), promotion of alveolar epithelial surfactant synthesis
Mansouri et al. 2019 [43]	Bone marrow MSCs	Fibrosis: in vivo mouse (BLM)	Lung tissue BAL	↓Arg-1, ↓CCL2	Reduction of inflammation (decreased pro-inflammatory cytokine and Arg-1), alveolar epithelial apoptosis, septal thickness, and pulmonary collagen deposition
Loy et al. 2019 [44]	Umbilical cord MSCs	ALI: in vitro human AECs (H5N1)	AECs	No particular mechanism studied	Restoration of alveolar fluid clearance and reduction of alveolar protein permeability
Li et al. 2019 [45]	Bone marrow MSCs	ALI: in vivo rat (Traumatic)	Lung tissue BAL	↓P2X7, ↓MDA, ↓H2O2, ↑GSH, ↑SOD, ↓TNF-α, ↓IL-6, ↓IL-8, ↑IL-10	Reduction of inflammation (decreased oedema and pro-inflammatory cytokines), capillary hyperaemia, and alveolar wall thickness
Varkouhi et al. 2019 [46]	γ–primed umbilical cord MSCs	ALI: in vivo rat (E. coli)	Lung tissue BAL	↑eNOS, ↓TNF-α	Increase of animal survival, reduction of inflammation (decreased pro-inflammatory cytokine, increase of macrophage bacterial phagocytosis), restoration of alveolar epithelial surfactant synthesis and pulmonary endothelial cell permeability, and reduction of alveolar wall thickness
Zhou et al. 2019 [47]	Umbilical cord EPC (rich in miR-126)	ALI: in vivo mouse (LPS)	Lung tissue BAL	↓TNF-α, ↓IL-6, ↓IL-1β, ↓IFN-γ, ↓MIP-1, ↓MIP-2, ↓MIG, ↓IP-10, ↓MPO	Reduction of inflammation (reduced pro-inflammatory cytokines and neutrophils in alveolar space), alveolar wall thickness, and hyaline membrane formation
		ALI: in vitro human AECs (LPS)	AECs	↑Claudin1, ↑Claudin4, ↑Occludin
Park et al. 2019 [48]	Bone marrow MSCs	ALI: ex vivo perfused human lung (E. coli)	Lung tissue BAL	TNF-α (no difference)	Antimicrobial effects (increased macrophages phagocytosis and decreased bacterial levels), restoration of alveolar epithelial surfactant synthesis and alveolar fluid clearance, reduction of pulmonary endothelial permeability and alveolar wall thickness
Royce et al. 2019 [49]	Amnion epithelial cells	Fibrosis: in vivo mouse (BLM)	Lung tissue	↓TGF- β	Reduction of tissue inflammation and myofibroblast accumulation
Sun et al. 2019 [50]	Menstrual blood-derived endometrial stem cells	Fibrosis: in vivo mouse (BLM)	Lung tissue	↓Hydroxyproline, ↓MDA, ↑Let-7	Reduction of inflammation (decreased inflammasome), DNA damage (decreased ROS) and collagen deposition
		Fibrosis: in vitro mouse AECs (BLM)	AECs	↓ROS, ↓LOX1, ↓NLRP3, ↓Hydroxyproline, ↓MDA, ↑Let-7
Liu et al. 2019 [51]	Umbilical cord MSCs	ALI: in vivo rat (Burn)	Lung tissue Serum	↓TNF-α, ↓IL-1β, ↓IL-6, ↑IL- 10, ↓MDA, ↓MPO, ↑SOD, ↓TLR4, ↓p-p65, ↑miR-451	Reduction of inflammation (lower pro-inflammatory cytokines and decreased immune cell recruitment)
Sun et al. 2018 [52]	Whole blood	Fibrosis: in vivo mouse (Zeocin)	Lung tissue	↓Hydroxyproline	Reduction of inflammation (decreased immune cell recruitment), alveolar wall thickness and collagen deposition
Bandeira et al. 2018 [53]	Adipose MSCs	Fibrosis/Silicosis: in vivo mouse (Silica)	Lung tissue	↓TGF-β, ↓TNF-α, ↓IL-1β	Reduction of inflammation (decreased pro-inflammatory cytokines and macrophages) and collagen deposition
Tan et al. 2018 [54]	Amnion epithelial cells	Fibrosis: in vivo mouse (BLM)	Lung tissue	↑CTNNB1, ↑BMP4, ↑BMPR1, ↑FOXM1, ↑LEF1, ↑NFATC1, ↑PGK1, ↑PTN, ↑SCA1, ↑WLS, ↓cMYC	Prevention and reduction of inflammation (lower CD4 + T cells and pulmonary interstitial macrophages) and collagen deposition
Hu et al. 2018 [55]	Bone marrow MSCs	ALI: in vitro human LMVECs (Cytomix)	LMVECs	↑VE-cadherin, ↑ZO-1, ↑p-myosin light chain 2, ↑Ang1, ↑S1PK	Decrease of microvascular permeability
Zhang et al. 2018 [56]	Pulmonary microvascular endothelial cells	ALI: in vivo mouse (LPS)	Lung tissue	↓TNF-α, ↓IL-1β, ↓IL-6	Reduction of inflammation (lower pro-inflammatory cytokines) and restoration of pulmonary endothelial function (rearranged cytoskeleton and decreased microvascular permeability)
			BAL	↓TNF-α, ↓IL-2, ↓IL-3, ↓IL-6, ↓GM-CSF, ↓CCL-2, ↓MCP-5, ↓CCL-5
Shah et al. 2018 [57]	Bone marrow MSCs	ARDS: in vivo mouse (LPS)	Lung tissue	↑Runx1p66/p52, ↑TβRI/Alk5	Reduction of perivascular area and interstitial thickness
Wu et al. 2018 [58]	Endothelial progenitor cells	ALI: in vivo rat (LPS)	Lung tissue	↑RAF, ↑ERK, ↓SPRED-1, ↓MDA, ↑miR-126	Enhancement of gas exchange (improved PaO2), reduction of inflammation (reduced oedema and neutrophil in alveolar space), regeneration of pulmonary endothelial cells and reduction of alveolar wall thickness
Khatri et al. 2018 [59]	Bone marrow MSCs	ALI: in vivo pig (Influenza)	Lung tissue BAL Nasal swabs	↓TNF-α, ↓CXCL10, ↑ IL-10	Reduction of inflammation (decreased pro-inflammatory cytokines and chemokines), lung endothelial cell apoptosis, alveolar wall thickness and collapse, and inhibition of influenza virus replication
		ALI: in vitro pig LECs (Influenza)	LECs	↓Apoptosis
Wang et al. 2017 [60]	Bone marrow MSCs	ALI: in vitro mouse PMVECs (LPS)	PMVECs	↑VE-cadherin, ↑ZO-1, ↓IL-6, ↑IL-10	Reduction of inflammation (decreased pro-inflammatory cytokines) and pulmonary endothelial permeability
Morrison et al. 2017 [61]	Bone marrow MSCs	ARDS: in vivo mouse (LPS)	BAL	↓TNF-α	Reduction of inflammation (lower pro-inflammatory cytokine and neutrophils in alveolar fluid)
Gao et al. 2017 [62]	Neutrophils loaded with piceatannol	ALI: in vivo mouse (LPS)	Lung tissue BAL Plasma	↓TNF-α, ↓IL-6, ↓MPO	Increase in animal survival, reduction of inflammation (lower pro-inflammatory cytokines, leukocytes and neutrophils in alveolar fluid) and pulmonary endothelial permeability
		ALI: in vitro human HUVECs (LPS)	HUVECs	↓ICAM-1, ↓IκBα, ↓p65
Tang et al. 2017 [63]	Bone marrow MSCs	ALI: in vivo mouse (LPS)	Lung tissue BAL	↓MIP-2	Reduction of inflammation (decreased pro-inflammatory cytokines, leukocytes and neutrophils in alveolar fluid), pulmonary endothelial permeability, and alveolar wall thickness
		ALI: in vitro human LMVECs and mouse RAW264.7 cells (LPS)	LMVECs RAW264.7	↓TNF-α, ↑IL-10
Ju et al. 2017 [64]	Urine-derived pluripotent stem cells	ALI: in vitro human MVECs (LPS)	MVECs	↓ICAM-1, ↓MPO	Reduction of inflammation (attenuated neutrophils adhesion and blocked inflammatory activation in the pulmonary endothelium)
Shentu et al. 2017 [65]	Bone marrow MSCs	Fibrosis: in vitro human LFCs	LFCs	↓αSMA, ↓Col IA1, ↓Col III A1	Reduction of myofibroblast accumulation and collagen deposition
Li et al. 2015 [66]	Bone marrow MSCs	ALI: in vivo mouse (E. coli)	BAL	↓MIP-2	Reduction of inflammation (decreased pro-inflammatory cytokines, leukocytes and neutrophils and increased anti-inflammatory cytokines in the alveolar fluid)
		ALI: in vitro mouse RAW264.7 cells (E. coli)	RAW264.7	↓TNF-α, ↑IL-10
Choi et al. 2015 [67]	S. aureus	Pneumonia: in vivo mouse (Staphylococcus aureus)	Lung tissue Blood	↓IL-1β, ↓IL-6, ↑IL-17, ↑IL-4, ↑IFN-γ	Increase in animal survival, reduction of inflammation (decreased pro-inflammatory cytokines) and induction of adaptative immunity (increased T cell response)
Monsel et al. 2015 [68]	Bone marrow MSCs	Pneumonia: in vivo mouse (E. coli)	Lung tissue BAL	↓MIP-2, ↑KGF, ↓TNF-α	Increase in animal survival and antimicrobial effect (increased monocyte phagocytosis), reduction of inflammation (lower pro-inflammatory cytokines and neutrophil in alveolar space), pulmonary endothelial permeability, and alveolar wall thickness
		Pneumonia: in vitro human AEC2 (LPS and Cytomix)	AEC2
Zhu et al. 2014 [69]	Bone marrow MSCs	ARDS: in vivo mouse (E. coli)	Lung tissue BAL	↓MIP-2	Reduction of inflammation (lower pro-inflammatory cytokines, leukocytes and neutrophils in alveolar fluid) and interstitial thickness
		ARDS: in vitro mouse RAW264.7 cells (E. coli)	RAW264.7	↑IL-10, ↓TNF-α, ↓MIP-2

Abbreviations:

AEC2: Alveolar epithelial cells type 2; AECs: Alveolar epithelial cells; ALI: Acute lung injury; ANG1: Angiopoietin 1; AQP: Aquaporin; ARDS: Acute respiratory distress syndrome; BAL: Bronchioalveolar lavage; BEAS-2B: Bronchial epithelial cells; BLM: Bleomycin; BMDMs: Bone marrow-derived macrophages; BMP: Bone morphogenetic protein; BMPR1: Bone morphogenetic protein receptor 1; COL: Collagen; CTNNB1: Catenin beta 1; CXCL: Chemokine (C-X-C motif) ligand; EPC: Endothelial progenitor cell; ERK1/2: Extracellular regulated kinase ½; EVs: Extracellular vesicles; FOXM: Forkhead Box M1; GM-CSF: Granulocyte macrophage colony stimulating factor; HGF: Hepatocyte growth factor; HUVECs: Human umbilical vein endothelial cells; ICAM-1: Intercellular adhesion molecule-1; IFN: Interferon; IL: Interleukin; IP: Interferon gamma-induced protein; IкBα: Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; JNK: c-Jun N-terminal kinases; KC: Keratinocyte chemoattractant; KGF: Keratinocyte growth factor; LECs: Lymphatic endothelial cells; LEF1: Lymphoid enhancer-binding factor-1; LFCs: Lung fibroblast cells; LMVEC: Lung microvascular endothelial cell; LOX1: Lectin-like oxidized LDL receptor-1; LPS: Lipopolysaccharide; LTB4: Leukotriene B4; MCP: Monocyte chemotactic protein; MDA: Malondialdehyde; MEK1/2: P-dual specificity mitogen-activated protein kinase ½; MIG: Monokine induced by gamma interferon; MIP: Macrophage induced protein; MIR: MicroRNA; MMP-9: Matrix metalloproteinase-9; MPO: Myeloperoxidase; MRC-1: Mannose Receptor C-Type 1; MRP1: Multidrug resistance associated protein 1; MSC: Mesenchymal stem/stromal cell; MVECs: Microvascular endothelial cells; NFATC1: Nuclear factor of activated T-cells, cytoplasmic 1; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR Family pyrin domain containing 3; NOS: Nitric oxide synthase (iNOS – inducible, eNOS – endothelial); P38MAPK: p38 mitogen-activated protein kinase; PGK1: Phosphoglycerate kinase 1; PM2.5: fine particulate matter; PMVECs: Pulmonary microvascular endothelial cells; PTN: Pleiotrophin; RAW267.4: Monocyte/macrophage lineage; ROS: Reactive oxygen species; S1PK: Sphingosine kinase; SAA3: Serum amyloid A3; SCA1: Stem cell antigen-1; SMA: Smooth muscle actin; SMAD3: Mothers against decapentaplegic homolog 3; SOD: Superoxide dismutase; SP-C: Surfactant protein-C; SPRED-1: Sprouty-related, EVH1 domain-containing protein 1; TGF: Transforming growth factor; THP-1: Human monocyte cell line; TLR: Toll-like receptor; TNF: Tumour necrosis factor; TRPV4: Transient receptor potential vanilloid 4; TβRI: Transforming growth factor-beta receptor I; VE-Cadherin: Vascular endothelial cadherin; VEGF: Vascular endothelial growth factor; VWF: Von Willebrand factor; WLS: Wnt Ligand Secretion Mediator; YM-1: Chitinase 3-like 3, a macrophage protein; ZO-1: Tight junction protein

Table 3. Articles comparing the effects of different EV populations.

Study	EV populations	EV treatment outcome summary
Dinh et al. 2020 [32]	LSC-EVs vs MSC-EVs	Both EV populations ameliorated lung fibrosis. LSC-EVs promoted more alveolar repair via increased aquaporins and had reduced SMAD3 levels compared to MSC-EVs
Yu et al. 2019 [34]	Mouse AT-EVs vs. S-EVs vs. ADSC-EVs	All EV populations restored adherens junction protein expression and attenuated inflammation. AT-EVs and ADSC-EVs were more efficient in suppressing endothelial inflammation than S-EVs
Huang et al. 2019 [35]	Human adipose MSC-EVs from young (25 years old) vs. old (72 years old) donors	Young (but not old) MSC-EVs alleviated ALI and altered macrophage phenotypes
Zhang et al. 2019 [37]	Mouse PMVECs with high vs. low syndecan-1	SDC1-high-EVs (but not SDC1-low-EVs) ameliorated lung inflammation by reducing pro-inflammatory cytokines
Kim et al. 2019 [39]	Human DMSC23-EVs vs. CMSC29-EVs	Both EV populations reduced pro-inflammatory cytokines and increased the migration of human bronchial epithelial cells
Yi et al. 2019 [40]	Mouse MSC-EVs with high vs. low miR-30b-3p	Only MSC-EVs with high miR-30b-3p levels increased cell proliferation and reduced cell apoptosis and pro-inflammatory cytokines
Varkouhi et al. 2019 [46]	Human interferon-γ-primed MSC-EVs vs. naïve MSC-EVs	Both EV populations enhanced survival and bacterial phagocytosis in THP-1 cells and reduced the alveolar wall thickness. Only IFN-γ-primed MSC-EVs decreased pro-inflammatory cytokines
Zhou et al. 2019 [47]	Human EPC-EVs vs. NIH3T3-EVs	EPC-EVs (but not NIH3T3-EVs) reduced pro-inflammatory cytokine and chemokine production and lung tissue injury and restored alveolar barrier
Tan et al. 2018 [54]	Human AEC-EVs vs. HLF-EVs	AEC-EVs and HLF-EVs similarly reduced neutrophil infiltration and interstitial macrophages. AEC-EVs were more effective in attenuating lung fibrosis in aged mice compared to HLF-EVs
Wang et al. 2017 [60]	Mouse HGF knockdown MSC-EVs vs. MSC-EVs	MSCs-EVs (but not HGF knockdown MSC-EVs) reduced pro-inflammatory cytokines and restored endothelial permeability regulation
Gao et al. 2017 [62]	Human NS-EVs vs. NC-EVs	NS-EVs and NC-EVs similarly reduced pro-inflammatory cytokines and leukocytes and restored alveolar epithelial function
Tang et al. 2017 [63]	Human Ang-1 knockdown MSC-EVs vs. MSC-EVs	MSC-EVs (but not Ang-1 knockdown MSC-EVs) reduced lung inflammation and pulmonary capillary permeability
Li et al. 2015 [66]	Human MSCIPC-30-EVs vs. MSCIPC-60-EVs vs. MSCIPC-90-EVs	MSCIPC-60-EVs were more effective at reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines than MSCIPC-30-EVs and MSCIPC-90-EVs
Monsel et al. 2015 [68]	Human MSC-EVs vs. NHLF-EVs	MSC-EVs (but not NHLF-EVs) increased survival rate and decreased pro-inflammatory cytokines
Zhu et al. 2014 [69]	Human MSC-EVs vs. NHLF-EVs	MSC-EVs (but not NHLF-EVs) reduced inflammation and protein permeability and decreased lung injury

Abbreviations

ADSC-EVs: Adipose-derived stem cell extracellular vesicles; AEC-EVs: Amnion epithelial cell extracellular vesicles; ALI: Acute lung injury; AT-EVs: Adipose tissue extracellular vesicles; BEAS-2B: Bronchial epithelial cell line; CMSC29-EVs: Chorionic-derived mesenchymal stem cell extracellular vesicles; DMSC23-EVs: Decidual-derived mesenchymal stem cell extracellular vesicles; EPC-EVs: Endothelial progenitor cell extracellular vesicles; EVs: Extracellular vesicles; HGF: Hepatocyte growth factor; HLF-EVs: Human lung fibroblast extracellular vesicles; LSC-EVs: Lung spheroid cell extracellular vesicles; MSC-EVs: Mesenchymal stem/stromal cell extracellular vesicles; MSCIPC-30-EVs: MSCs subjected to Ischaemic Pre-Conditioning for 30 minutes-derived extracellular vesicles; MSCIPC-60-EVs: MSCs subjected to Ischaemic Pre-Conditioning for 60 minutes-derived extracellular vesicles; MSCIPC-90-EVs: MSCs subjected to Ischaemic Pre-Conditioning for 90 minutes-derived extracellular vesicles; NC-EVs: Nitrogen cavitation generated extracellular vesicles; NHLF-EVs: Normal human lung fibroblasts; NIH3T3-EVs: fibroblast-derived extracellular vesicles; NS-EVs: Naturally secreted extracellular vesicles; PMVEC-EVs: Pulmonary microvascular endothelial cell extracellular vesicles; SDC1: Gene for encoding syndecan-1; S-EVs: Serum-derived extracellular vesicles

Table 4. Details of EVs used as a therapy in lung injury models.

Study	EV source	EV separation	EV characterization	EV dosage
Wang et al. 2020 [31]	Adipose MSCs	Pre-clearing cells/debris, UC (118,000 g for 16 h at 4°C)	NTA; DLS; TEM; Flow Cytometry (CD63); WB (CD40, CD44, CD63, CD81, CD105; GM130, Calnexin)	1 dose; 100 μg/mL of EVs added to culture medium, or 50 µg/0.05 ml of EVs, administered via intratracheal injection (in vivo)
Dinh et al. 2020 [32]	Lung spheroid cells	Ultrafiltration, Centrifugation (5000 g for 10–15 min)	NTA; TEM; WB (CD63, CD81, TSG101)	1 dose; 10 × 10^9 particles per kg of body weight, administered intranasally (aerosolized)
Gao et al. 2020 [33]	Adipose MSCs	Ultracentrifugation (details unspecified)	NTA; TEM; WB (CD63, TSG101, Alix, GM130)	1 dose; 1 × 10^9 EVs added to culture medium, or 2.5 ~ 2.8 × 10^10 EVs in 20 μL PBS, administered via intratracheal injection (in vivo)
Yu et al. 2020 [34]	Adipose tissue, Adipose MSCs, Serum	Pre-clearing cells/debris, TEIR	NTA; TEM; WB (CD63, HSP70, TSG101)	1–2 doses; 0, 25, 50, and 100 μg/ml of EVs added to culture medium or injected intravenously 1 h before and immediately after mechanical ventilation
Huang et al. 2019 [35]	Adipose MSCs	Pre-clearing cells/debris, UC (118,000 g for 16 h at 4°C)	NTA; TEM; WB (CD63, CD81, CD105, CD44, GM130, Calnexin)	1 dose; 100 μg/200 µl of EVs, administered via tail vein injection
Silva et al. 2019 [36]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; SEM	1 dose; EVs from 10^5 cells, administered via jugular vein injection
Zhang et al. 2019 [37]	PMVECs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; TEM; WB (CD9, CD63, CD81)	2 doses; 3 μg/g of EVs, administered via tail vein injection
Hao et al. 2019 [38]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; SEM; Flow Cytometry (CD9, CD44)	1–4 doses; 3, 6, and 12 × 10^8 particles added to culture medium, or 90 µl of EV per mouse (1x10^10 particles), administered intravenously (in vivo)
Kim et al. 2019 [39]	Placental chorionic or decidual MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; TRPS; SEM; TEM; AFM	1–2 doses; ranging 6 × 10^5–1.5 × 10^7 particles per ml, added to culture medium
Yi et al. 2019 [40]	Bone marrow MSCs	Pre-clearing cells/debris, centrifugation (10,000 g for 1 h at 4°C, twice)	NTA; Flow Cytometry (CD63)	1 dose; 1 μg/100 μL or 100 μg/200 μL, administered via intravenous injection (caudal veins)
Chen et al. 2019 [41]	Umbilical cord MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	SEM; Flow Cytometry (CD34, CD44, CD45, CD73, CD105)	1 dose; 4 mg/kg, administered via intratracheal injection
Xu et al. 2019 [42]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; TEM; WB (CD9, CD63, CD81)	1 dose; EVs from 5 × 10^6 cells, administered via intratracheal injection
Mansouri et al. 2019 [43]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 3.5 h at 4°C)	NTA, TEM, WB (Alix, CD63, CD9, Flot-1)	1 dose; diluted in PBS to correspond to 5 × 10^6 cell equivalent, administered via intravenous injection
Loy et al. 2019 [44]	Umbilical cord MSCs or bone marrow MSCs	Pre-clearing with filtration; ExoEasy Maxi Kit, miRCURY Exosome Isolation Kit	Not specified	1 dose; not specified concentration of EVs, administered via intravenous injection
Li et al. 2019 [45]	Bone marrow MSCs	Pre-clearing cells/debris, centrifugation (12,000 g for 1 h at 4°C, twice)	NTA; TEM; WB (CD9, CD63, CD81)	2 doses per day for 7 days; 25 μg of EVs, administered via tail vein injection
Varkouhi et al. 2019 [46]	γ–primed umbilical cord MSCs	Pre-clearing cells/debris, UC (100,000 g for 1.5 h at 4°C)	TEM; Flow Cytometry for size	1 dose; 10 × 10^8 EVs/kg, administered via intravenous injection
Zhou et al. 2019 [47]	Umbilical cord EPCs	Pre-clearing cells/debris, TEIR	NTA; WB (CD9, CD63, CD81)	1 dose; 70 μg of EVs, administered via intratracheal injection
Park et al. 2019 [48]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; SEM; Flow Cytometry (CD9, CD44);	1 dose; 200 μl – 400 μl of EVs, administered via intravenous injection
Royce et al. 2019 [49]	Amnion epithelial cells	Not specified	Not specified	1 dose; 5–25 μg of EVs, administered intranasally
Sun et al. 2019 [50]	Menstrual blood-derived endometrial stem cells	TEIR	NTA; TEM; WB (TSG101, CD9, CD63, Calnexin)	1 dose; 0.5 mg/kg of EVs, administered via tail vein injection
Liu et al. 2019 [51]	Umbilical cord MSCs	Pre-clearing cells/debris, ExoQuick	NTA; TEM; WB (CD9, CD63)	1 dose; 800 μg of EVs, added to culture medium, or administered via tail vein injection (in vivo)
Sun et al. 2018 [52]	Whole blood	Sonication, Ultrafiltration (9,000 g for 15 min)	TEM; AFM	2 doses; 2.5 mg/kg and 0.25 mg/kg of EVs, administered intranasally (nasal drip)
Bandeira et al. 2018 [53]	Adipose MSCs	Pre-clearing cells/debris, UC (100,000 g for 2 h)	TEM; NTA, WB (CD63, CD81, LAMP-1, CD9)	1 dose; 50 µl of EVs, administered via intratracheal injection
Tan et al. 2018 [54]	Amnion epithelial cells	Centrifugation (details unspecified)	NTA; TEM; WB and Flow cytometry (CD9, CD81, Alix, HLA-G)	1 dose; not specified concentration of EVs, added to culture medium
Hu et al. 2018 [55]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	NTA; SEM; Flow Cytometry (CD9, CD44)	1–2 doses; 30 µl or 60 µl of EVs, added to culture medium
Zhang et al. 2018 [56]	Serum	TEIR	NTA; TEM; WB (CD63, Flot-1, TSG101)	1 dose; 10 μl – 500 μl of EVs, administered via intratracheal injection
Shah et al. 2018 [57]	Bone marrow MSCs	Pre-clearing cells/debris, UC (28,000 g for 2 h at 4°C, twice)	NTA; Flow Cytometry for size	2 doses; 2.9 × 10^5 and 5.8 × 10^5 of EVs in 100 μl PBS, administered via retroorbital injection
Wu et al. 2018 [58]	Endothelial progenitor cells	Pre-clearing cells/debris, UC (100,000 g for 2 h at 4°C, twice)	NTA; TEM; WB (CD63, Alix, TSG101)	1 dose; 100 μg, administered via tail vein injection
Khatri et al. 2018 [59]	Bone marrow MSCs	Pre-clearing cells/debris, UC (25,000 g for 70 min at 4°C)	TEM; WB (CD9, CD63, CD81)	1 dose; 10 μg/mL of EVs added to culture medium, or 80 μg/kg of EVs, administered via intratracheal injection
Wang et al. 2017 [60]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	Flow Cytometry (CD29, CD34, CD44, CD45, CD105) TEM; SEM;	1 dose; unspecified concentration of EVs, added to culture medium
Morrison et al. 2017 [61]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 2 h)	Flow Cytometry for size and CD44	1 dose; unspecified concentration of EVs added to different models, administered intranasally (in vivo)
Gao et al. 2017 [62]	Neutrophils	NS-EVs: pre-clearing cells/debris, UC (100,000 g for 1 h). NC-EVs: nitrogen cavitation chamber at a pressure of 400–500 psi for 20 min at 0°C	qNano and dynamic light scattering; cryo-TEM for NC-EVs; WB (IntegrinB2, LAMP-1, Calnexin, COXIV)	1 dose; unspecified number of drug loaded EVs (piceatannol at 3 mg/kg), administered via intravenous injection
Tang et al. 2017 [63]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	TEM and SEM	Not specified
Ju et al. 2017 [64]	Urine-derived pluripotent stem cells	Pre-clearing cells/debris, UC (120,000 g for 70 min at 4°C, twice)	NTA; TRPS; TEM; WB (CD63, TSG101, Alix)	1 dose; 10 μg protein of Exo/siRNA (EV) compound or micropoly with siRNA at a final concentration of 100 nM, added to culture medium
Shentu et al. 2017 [65]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 for 1 h, twice)	NTA; TEM; WB (CD63, CD81, Calnexin)	1 dose; 10 μg of EVs added to culture medium
Li et al. 2015 [66]	Bone marrow MSCs	ExoQuick	WB (CD63)	1 dose; 1.5 μg/g of EVs, administered via tail vein injection
Choi et al. 2015 [67]	S. aureus	Pre-clearing cells/debris, UC (150,000 g for 3 h at 4°C)	Not specified	1 dose; 10 μg/ml of EVs added to culture medium
Monsel et al. 2015 [68]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C)	TEM, WB (CD44)	3 doses; EVs from 10 μL per 1 × 10^6 cells added to culture medium, or EVs administered intratracheal (30 µl or 60 µl) or intravenously (90 µl) (in vivo)
Zhu et al. 2014 [69]	Bone marrow MSCs	Pre-clearing cells/debris, UC (100,000 g for 1 h at 4°C, twice)	TEM and SEM	1–2 doses; 30 µl or 60 µl of EVs, administered via intravenous or intratracheal injection

Abbreviations: AFM: Atomic force microscopy; Alix: Apoptosis-Linked Gene 2-Interacting Protein X; CD: Cluster of differentiation; COXIV: Cytochrome c oxidase Complex IV; DLS: Dynamic light scattering; EV: Extracellular vesicle; Flot-1: Flotillin 1; GM: Golgi matrix; HLA: Human leukocyte antigen; HSP: Heat shock protein; IntegrinB2: Integrin beta 2; LAMP-1: Lysosome-associated member glycoprotein 1; MSC: Mesenchymal stromal/stem cell; NTA: Nanoparticle tracking analysis; PMVEC: Pulmonary microvascular endothelial cell; SEM: Scanning electron microscopy; TEIR: Total exosome isolation reagent; TEM: Transmission electron microscopy; TRPS: Tunable resistive pulse sensing; TSG: Tumour susceptibility; UC: Ultracentrifugation; WB: Western blot

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