The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis

Zhang, Xuefeng; Cheng, Zongyong; Zeng, Menghao; He, Zhihui

doi:10.1186/s12890-024-02910-4

BMC Pulmonary Medicine

Table 1 Abbreviations: ADMSC adipose derived mesenchymal stromal cells, BMSC bone marrow mesenchymal stromal cells, C control group, CLP caecal ligation and puncture,EPC endothelial progenitor cell, EVs extracellular vesicles, MVs microvesicles, 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 BLM: bleomycin LPS: lipopolysaccharide SwIV: swine/MN/08; H1N1 MDR-P: multidrug-resistant PA

From: The efficacy of extracellular vesicles for acute lung injury in preclinical animal models: a meta-analysis

Author	Country or region	Injury type	Species	Sex	Cell source of EVs	Diameter (nm)	Administration methods	Therapy time	Measurement time	Dose	Main finding
Buesing, Keely L [29]	USA	it lps	C57BL/6 J	male	UVECl	< 300	iv	24 h	24 h	20,000/ml	EMPs are significant contributors to ALI via inflammatory cytokines, resultant neutrophil recruitment, and ultimately increases in MPO levels in the lung tissue
Chang, Chia-Lo [30]	China	CLP	SD rats	male	ADMSCs	30–90	iv	117 h	120 h	50ug	Not only localized but also systemically inflammatory reactions were elicited by SS. Apoptotic ADMSC-derived exosomes might be inferior to healthy ADMSC-derived exosomes for reducing the multi-organ damage and mortality rate in rodents after SS
Chen, W [31]	China	it BLM	SD rats	male	WJMSCs	200	it	24 h	48 h	NR	HGF mRNA partly mediated the therapeutic effects of MSC-MVs on ALI in mice induced by BLM via PI3K-Akt-mTOR activation
Chen, W [32]	China	it BLM	SPF rats	male	WJMSCs	200	it	5d	7d	10ul	WJMSC-MV-transferred miR-100 mediated, at least in part, the therapeutic effect of WJMSC-MVs in ALI through restoring mTOR signalmediated inhibition of autophagy
Deng, H [33]	China	injected intraperitoneally lps	C57BL/6 J	male	BMSCs	80–150	it	23 h	24 h	100ug	BMSCs-derived exosomes inhibited the inflammatory response and regulated macrophage polarization possibly through inhibiting HIF-1amediated glycolysis
Deng, H [34]	China	injected intraperitoneally lps	C57BL/6 J	male	ADMSCs	40–150	it	23 h	24 h	100ug	Exosomes derived from hMSCs from adipose tissue exhibited particularly strong effects in promoting macrophage M2 polarization, inhibiting proinflammatory cytokine production
Huang, R [35]	China	it lps	C57BL/6 J	NR	ADMSCs	50–400	iv	47.5 h	48 h	100ug	Aging MSC-EVs had higher levels of miR-127-3p and miR-125b-5p (M1) compared with young MSC-EVs. This finding might explain the observed difference in M2 macrophage polarization between aging and young MSC-EVs
Kaspi, Haggai [36]	USA	it lps	C57BL/6 J	female	BMSCs	146	it	69 h	72 h	50ul	Exo MSC-NTF reduced neutrophil count, TF, and fibrin, in the lung tissue, thereby interrupting a disease cascade that may explain the early lung recovery or the prevention of damage following intratracheal exosome treatment.
Khatri, M [37]	USA	it SwIV	White-Duroc crossbred pigs	NR	BMSCs	100	it	60 h	72 h	80ug/Kg	EVs derived from porcine BM-MSCs inhibit the HA activity of influenza viruses and SwIV replication and virus-induced apoptosis in LECs
Li, Qing-Chun [38]	China	struck the chest	SPF rats	NR	BMSCs	30–50	iv	7d30min	7d	25ug	MiR-124-3p transferred by MSC-derived exosomes inhibits the expression of P2X7, thus alleviating OS injury and inflammatory response in rats with traumatic ALI
Liu, F [39]	China	CLP	SD rats	NR	Alveolar Epithelial Cel	100	it	24 h	24 h	2 mg/Kg	Exosome-shuttled miR-92a-3p mediated the crosstalk between AECs and AMs, which contributes to macrophage activation by inhibiting PTEN expression and regulating the activation of the NF-kB signalling pathway
Liu, Jian-Hua [40]	China	it lps	C57BL/6 J	male	BMSCs	50–200	iv	44 h	48 h	100ug	Exosomal miR-132-3p ameliorated LPSinduced ALI via targeting TRAF6 and inactivating PI3K/Akt signalling
Liu, X [41]	China	it lps	SD rats	male	BMSCs	63–269	it	20 h	24 h	50ul	BMSC-derived exosomes alleviate LPSinduced autophagy stress of alveolar macrophages, at least partly, via delivering exosomal miR-384-5p to alveolar macrophages
Mao, Guan-chao [42]	China	inject the Sulfur mustard on the surfaces	ICR mice	male	BMSCs	30–100	iv	96 h	120 h	20 mg/Kg	The antiapoptotic and barrier-regenerating effects of BMSC-Exs may be mediated by the upregulation of GPRC5A expression in recipient cells, which activates the YAP pathway, leading to the promotion of Bcl-2 and junction protein expression and relocalization
Monsel, Antoine [14]	France	it lps	C57BL/6 J	male	BMSCs	200	it	20 h	24 h	60ul	MV released from BMSCs improved survival from E.coli pneumonia in mice. This was associated with enhanced phagocytosis of bacteria by human monocytes with a reduction in inflammation and increased ATP levels in alveolar epithelial type 2 cells
Morrison, T. J [43]	UK	intranasally lps	C57BL/6 J	male	BMSCs	< 4000	intranasally	20 h	24 h	NR	MSCs modulate human macrophages towards decreased production of proinflammatory cytokines, increased expression of the M2 phenotype marker CD206 and enhanced phagocytic capacity. MSC-EVs carrying mitochondria are responsible for these effects through the promotion of oxidative phosphorylation in macrophages
Shi, Meng-meng [44]	China	it MDR-P	C57BL/6 J	male	ADMSCs	50–400	it	20 h	24 h	NR	MSCs and miR-466 promoted macrophage polarization toward Type 2 phenotype through TIRAPMyD88-NFκB axis
Silva, J. D [45]	Brazil	it lps	C57BL/6 J	female	BMSCs	193.7–670.1	iv	24 h	48 h	50ul	MSCs yielded greater overall improvement in ARDS in comparison to EVs derived from the same number of cells and regardless of the preconditioning status
Silva, J. D [46]	UK	it lps	C57BL/6 J	male	BMSCs	100–700	iv	20 h	24 h	5*10^5 particles	MSC-EVs downregulate LPS-induced inflammatory response and attenuate mitochondrial dysfunction in human PCLSs. Therapeutic effect of MSC-EVs on the restoration of barrier integrity is mediated by mitochondrial transfer
Soni, S [47]	UK	it lps	C57BL/6 J	male	Alveolar macrophage	< 1000	it	4 h	4 h	NR	MVs released in vitro from LPS-primed alveolar macrophages caused similar increases in MLE-12 ICAM-1 expression, which was mediated by TNF
Tang, Xiao-Dan [48]	China	it lps	C57BL/6 J	male	BMSCs	200	it	48 h	48 h	30ul	The therapeutic effects of microvesicles in acute lung injury, and their immunomodulatory properties on macrophages were partly mediated through their content of Angiopoietin-1 mRNA
Varkouhi, Amir K [49]	Canada	it lps	SD rats	male	UCMSCs	47.7 ± 25.2	it	48 h	48 h	NR	The mechanistic insights into the actions of mesenchymal stromal cell–derived extracellular vesicles, namely enhancement of macrophage phagocytosis and killing of bacteria and restoration of endothelial nitric oxide synthase, which may restore capillary endothelial barrier function
Wang, Jiangmei [50]	China	it lps	C57BL/6 J	NR	BMSCs	50–150	it	48 h	48.5 h	50ug	Mesenchymal stem cell–derived extracellular vesicles mitigate acute lung injury at least partially via transferring miR-27a-3p to alveolar macrophages. miR-27a-3p acts to target NFKB1 and is a crucial regulator of M2 macrophage polarization
Wu, X [51]	China	it lps	SD rats	male	Bone endothelial progenitor cells	30–110	iv	48 h	48 h	100ug	MiR-126 of exosomes probably modulated the proliferation, migration and tube formation of ECs partly through directly inhibiting SPRED-1, so that to activate the RAF/ERK signaling
Xia, L [52]	China	it lps	C57BL/6 J	female	ADMSCs	50–150	iv	20 h	24 h	10ug	AdMSC-Exos can effectively donate mitochondria component improved macrophages mitochondrial integrity and oxidative phosphorylation level, leading to the resumption of metabolic and immune homeostasis of airway macrophages and mitigating lung inflammatory pathology
Xu, J [53]	China	it lps	C57BL/6 J	male	BMSCs	30–100	iv	48 h	48 h	100ug	Exosomes and miR-150 reduced inflammation and lung edema while maintaining the integrity of the alveolar structure. They also mitigated microvascular endothelial cell injury by regulating the caspase-3, Bax/Bcl-2, and MAPK signaling
Xu, N [54]	China	expose to the phosgene	SD rats	male	BMSCs	50–200	iv	24 h	24 h	50ul	MSC derived exosomes exerted the therapeutic effects on phosgene-induced ALI through inhibiting MMP-9 synthesis and up-regulating SP-C
Xu, Xinyi [55]	China	it lps	C57BL/6 J	male	Alveolar macrophage	200	it	24 h	24 h	NR	Secretory Autophagosomes from Alveolar Macrophages Exacerbate Acute Respiratory Distress Syndrome by Releasing IL-1β
Zhang, L [56]	China	it lps	C57BL/6J	NR	Alveolar macrophage	100	it	4 h	4 h	50ug	According to our results, inflammatory AM-derived MVs may potentially contribute to lung injury and pulmonary edema, thereby indicating a potential novel therapeutic approach against ALI/ARDS based on AM-MVs
Zhao, R [57]	China	it lps	C57BL/6 J	male	WJMSCs	82.5–164.1	iv	20 h	24 h	50ug	The inhalation of MSC-EVs presented better performance than those administered via tail vein injection for the treatment of ALI, as well as exhibited robust antiinflammatory and antioxidative activity in LPS-stimulated cells and animal models
Zhu, Ying-gang [14]	China	it lps	C57BL/6 J	male	BMSCs	200	it	36 h	48 h	30ul	Human MSC-derived MVs were therapeutically effective following E. coli endotoxin-induced ALI in mice in part through the expression of KGF mRNA in the injured alveolus

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