Roles and therapeutic potential of different extracellular vesicle subtypes on traumatic brain injury

Dong, Xinlong; Dong, Jing-fei; Zhang, Jianning

doi:10.1186/s12964-023-01165-6

Cell Communication and Signaling

Table 1 PEV mediates pathological damages after TBI^a

From: Roles and therapeutic potential of different extracellular vesicle subtypes on traumatic brain injury

EV Sources: Cell type/ Tissue /Species	Subset of PEV	Key component of PEV	Animal model/ sampling time point	PEV mediates pathological damages	Mechanisms/Main findings	Ref
Neurons and glial cells/ brain, plasma/Mouse	BDEV, PS⁺EV, TF⁺EV	PS and TF on membrane	TBI/0.5,1,3 and 6 h post-injury	•Coagulopathy •Systemic complications	•The traumatized brain releases procoagulant BDMPs into the circulation to trigger a disseminated coagulation cascade •The abundance of PS and TF on the membrane surface is responsible for the procoagulant activity of BDMP	Ye Tian et al. [23]
Neurons and glial cells/ plasma/ Mouse	CL⁺ mitochondrion	CL on mitochondrial membrane	TBI/0.25, 0.5,1,3,7,10,14 days post-injury	•Coagulopathy •Systemic complications	•The mtMP is a major subset of BDEVs •Abundant CL on the membrane surface is responsible for mtMPs-triggered coagulation dysfunction after TBI	Zilong Zhao et al. [24]
Neurons and glial cells/ plasma/ Mouse	BDEV, PS⁺EV	PS on membrane	TBI/3,24 h;1,2,3 days post-injury	•Coagulopathy •Systemic complications	•The assembly of Tenase on PS is an important reason for the extrinsic coagulation cascade reaction triggered by BDEV/PS⁺EV •ANV-6L15 prevents the assembly of Tenase on PS to inhibit coagulopathy and systemic complications after TBI	Xinlong Dong et al. [25]
Neurons and glial cells/ plasma/ Mouse	BDEV, PS⁺EV	PS on membrane	TBI/3,6 h;1,3,7 days post-injury	•Coagulopathy •Systemic complications	Lactadherin promotes the clearance of BDEVs by macrophages	Yuan Zhou et al. [26]
Neurons and glial cells/ brain, plasma/ Mouse	CL⁺ mitochondrion	CL on mitochondrial membrane	TBI/3 h post-injury	Coagulopathy	Extracellular mitochondria bind platelets through phospholipid-CD36 interactions and induce α-granule secretion, vesicle formation, and procoagulant activity	Zilong Zhao et al. [27]
Neurons and glial cells/ brain, plasma/ Mouse	BDEV, PS⁺EV	PS on membrane	TBI/3,6 h post-injury, 12 h after BDEV infusion	Impair cerebrovascular autoregulation	BDEVs cause sudden death in mice by inducing severe vasoconstriction	Jiwei Wang et al. [28]
blood cells /plasma/ Mouse	Circulating EVs	Specific miRNA and chemokines	TBI/2, 6, 12 and 24 h post-injury	•Dysregulated inflammatory •Systemic complications	The number of circulating EVs increases after TBI, along with increased numbers of leukocytes in the CNS and liver, exacerbating the acute-phase response	Isla Hazelton et al. [29]
Neurons and glial cells/brain/ Mouse	BDEV	Proinflammatory cytokine IL-1β, inflammasome components and MHCII proteins, etc	Stroke/ 1, 3, 7 and 14 days after surgery	Dysregulated inflammatory	•BDMPs exacerbate neuroinflammation and aggravate ischemic brain injury after stroke •Lactadherin exerts anti-inflammatory effects and increases EV clearance, thereby reducing BDEV-induced neurological deficits after stroke	Chen Z et al. [30]
BV2 microglia/culture medium/Mouse	Microglial-derived EV	Pro-inflammatory molecules	TBI/24 h post-injury	Dysregulated inflammatory	EVs loaded with pro-inflammatory molecules can activate microglia after TBI, which may exacerbate neuroinflammatory and systemic immune responses	Kumar A et al. [31]
Brain cells/Brain/Rat	BDEV	EVs-associated miR142	TBI/2 weeks post-injury	Dysregulated inflammatory	EVs-associated miR142 in the cerebral cortex surrounding the traumatic lesion in rats 2 weeks after TBI may further enhance the pro-inflammatory response of activated astrocytes in the region	Korotkov A et al. [32]
PC12 cells/culture medium/Rat	Neuron-derived EVs	miR-21-5p	TBI/3 days after administration	Dysregulated inflammatory	Neuron-derived EVs containing miR-21-5p induced microglial polarization, promoted the release of neuroinflammatory factors and exacerbated neuronal injury	Yin Z et al. [33]
Astrocytes/culture medium/ human	Astrocytes-derived EVs	Specific subset of miRNAs	—	Dysregulated inflammatory	Astrocyte-derived EVs express a specific subset of miRNAs that may play a potential role in modulating inflammatory responses	Manoshi Gayen et al. [34]
Neurons/ brain/ Mouse	Neurons-derived EV	miR-21	TBI/1–7 days post- injury	Dysregulated inflammatory	miR-21 as a potential cargo of neuron-derived EVs may mediate the activation of microglia	Harrison EB et al. [35]
EV in circulating blood /serum /Mouse	Serum-derived EVs	Inflammasome protein	TBI/4 and 24 h post-injury	•Dysregulated inflammatory •Systemic complications	•TBI induces EVs containing inflammasome proteins to target the lung and cause acute lung injury •Low-molecular-weight heparin blocks EV uptake by recipient cells and thereby inhibits inflammasome activation in the lungs of mice	Kerr NA et al. [36]
Neurons and glial cells, Platelet, Endothelial cells/ plasma/ Mouse	BDEV, pEVs, eEVs	VWF-bound EVs	TBI/1,3,4,6,12,24,36,48,72 h post-injury	•BBB disruption •Coagulopathy •Systemic complications	•Plasma VWF binds EVs to form VWF-EV complexes, disrupting the integrity of the BBB and increasing its permeability after TBI •rADAMTS-13 enhances VWF cleavage to preserve BBB integrity and prevent TBI-induced coagulopathy	YingangWu et al. [37]
Brain endothelial cells/ plasma/Mouse	eEVs	Tight junction proteins	TBI/24 h post-injury	•BBB disruption	Brain endothelial cells release eEVs containing TJP and endothelial markers to mediate vascular remodeling after TBI	Andrews AM et al. [38]
Brain endothelial cell/plasma/Rat	eEVs	—	Focal inflammatory brain lesions, 2 and 4 h after administration	•Dysregulated inflammatory •Systemic complications	Focal brain injury increased release of EV and initiated an acute-phase response in the liver	Couch Y et al. [39]
Neuroblastoma N2a cells/culture medium/Mouse	Neuroblastoma-derived EVs	Abeta peptides	—	Neurological disorders associated with TBI	EVs carrying Abeta peptides mediate the occurrence of AD	Rajendran L et al. [40]
Neuroblastoma M1C cells/culture medium/ Human	Neuroblastoma-derived EVs	tau protein	—	Neurological disorders associated with TBI	The mechanism by which the majority of tau secreted by M1C cells is released by EVs may explain the unconventional secretion of other aggregation-prone proteins in neurodegenerative diseases	Saman S et al. [41]
SH-SY5Y cells/culture medium/Human	Neuroblastoma-derived EVs	Alpha-synuclein	—	Neurological disorders associated with TBI	Alpha-synuclein released by EVs contributes to the amplification and dissemination of Parkinson's disease-associated pathology	Emmanouilidou E et al. [42]
SH-SY5Y cells were mixed cells expressing TDP-43/Culture medium/Huamn	EV from cells expressing TDP-43	TDP-43	—	Neurological disorders associated with TBI	EVs may contribute to the release of intracellular TDP-43 aggregates to mediate the occurrence of amyotrophic lateral sclerosis	Nonaka T et al. [43]
SH-SY5Y cells/culture medium/Human	Neuroblastoma-derived EVs	Alpha-synuclein	—	Neurological disorders associated with TBI	Alpha-synuclein in EVs aggregates more easily than cytosolic proteins, and aggregated alpha-syn is also released by cells	Lee HJ et al. [44]
Human H4 neuroglioma cells and neurons from mouse/culture medium	Neuroglioma- and neurons-derived EVs	Alpha-synuclein	—	Neurological disorders associated with TBI	Compared with free αsyn oligomers, EV-associated αsyn oligomers were more easily taken up and more toxic to recipient cells	Danzer KM et al. [45]
HEK-293 cells and neurons from mouse/culture medium	HEK-293 cells- and neurons-derived EVs	TDP-43	—	Neurological disorders associated with TBI	Compared with free TDP-43, TDP-43 in EVs was not only preferentially taken up by recipient cells, but also more toxic to recipient cells	Feiler MS et al. [46]
EV in circulating blood /plasma/human	LEVs and SEV in peripheral circulation	Specific mRNA and lncRNA	—	Neurological disorders associated with TBI	Analysis of SEV and LEV cargoes suggests that RNA may serve as novel, readily accessible biomarkers for AD, PD, ALS, and FTD in the future	Sproviero D et al. [47]

^aAbbreviations: AD Alzheimer's disease, ALS amyotrophic lateral sclerosis, ANV-6L15: ANV-6L15 fusion protein, BBB blood–brain barrier, BDEV brain-derived extracellular vesicles, CL cardiolipin, CL⁺mitochondrion CL-enriched mitochondrion, CNS central nervous system, eEVs endothelial-derived extracellular vesicles, EVs extracellular vesicles, FTD frontotemporal dementia, IL-1β interleukin-1β, LEVs large extracellular vesicles, mtMP mitochondrial microparticles, PD Parkinson's disease, PEV Pathological extracellular vesicles, pEVs platelet-derived extracellular vesicles, PS phosphatidylserine, PS⁺EV PS-enriched extracellular vesicles, rADAMTS-13 A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats, member 13, SEV small extracellular vesicles, TBI Traumatic brain injury, TDP-43 TAR DNA-binding protein of 43 kDa, TF tissue factor, TF⁺EV TF-enriched extracellular vesicles, TJP Tight junction proteins, VWF von Willebrand factor

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