Update on the roles and applications of extracellular vesicles in depression

Table 1 The Extracellular vesicles from different sources and their functions/applications in depression

Sources	EVs types	Cargos	Alternations	Roles/functions	Potential applications	Ref.
Cells-derived EVs
Astrocytes	Exosomes	ApoD	↑	Mediate neuronal survival upon oxidative stress	Therapeutic target	[25]
	EVs	VEGF	↑	Maintaining the BBB permeability	Biomarkers	[27]
	EVs	Inflammatory markers (Interferon-γ, IL-12p70, IL-1β, IL-2, IL-4, IL-6, TNF-α, IL-17A)	↑	Promote neuroinflammation	Biomarkers	[29]
Neurons	EVs	miR-135a-3p, miR-6790-3p, miR-11399	↑	Suppress neuronal functions	-	[30]
	Exosomes	miR-9-5p	↑	Promote microglia polarization through the SOCS2-STAT3 axis and neuronal injury	Therapeutic target	[31]
	EVs	miR-17-5p	↑	-	Diagnosis biomarkers	[32]
	EVs	miR-93	↓	Lead to interoceptive processing dysfunctions through altered epigenetic modulation of insular function	Therapeutic target	[33]
	EVs	miR-132-5p, miR-218-5p, miR-690	↑	Increase synaptic transmission and synchronous neuronal activity	-	[35]
	EVs	Mitochondrial proteins	↑/↓	Regulate neuronal metabolism and survival	Biomarkers and drug targets	[40]
	Exosomes	IRS-1	↑	Regulate central insulin signaling	Therapeutic target	[38]
	EVs	miR-21-5p, miR-30d-5p, miR-486-5p	↑	-	Biomarker for ADT response	[36]
	Exosomes	IL-34/CD81, synaptophysin/CD81	↑	Regulate neuroinflammation and synaptic functions	Biomarkers	[37]
Microglia	EVs	miR-146a-5p	↑	Inhibit neurogenesis	Biomarkers and therapeutic target	[41]
	Exosomes	VDBP	↑	-	Biomarker	[44]
Oligodendrocytes	Exosomes	PLP, CNP, MBP, MOG	↑	Promote myelin synthesis and turnover	-	[46]
	Exosomes	SIRT2	↑	Restore hippocampal neurogenesis and synaptic plasticity via the AKT/GSK-3β pathway	Therapeutic target	[47]
Anterior cingulate cortex	EVs	miR-92a-3p, miR-129-5p	↑	Involve neurotransmission and synaptic plasticity	-	[48]
Brain tissues	Exosomes	miR-210-5p, miR-143-5p, miR-574-5p, miR-551b-3p, let-7a-2-3p, etc.	↑/↓	Involve neuroplasticity, insulin resistance, and hypoxic response	Biomarkers	[49]
MSCs	Exosomes	miR-132	↑	Reduce neuroinflammation and protect the integrity of BBB	Diagnosis and therapeutic target	[52]
BMSCs	Exosomes	miR-26a	↑	Inhibit oxidative stress and inflammation, boost neuron proliferation and restrain apoptosis	Therapeutic target	[53]
ASCs	EVs	-	-	Inhibition of ER stress-mediated apoptotic	Therapeutic target	[54]
NSCs	EVs	miR-16-5p	↑	Neuroprotection	-	[55]
Macro-phages	Exosomes	LFA-1, ICAM-1, BDNF	↑	Mediate its lateral migration and crossing the BBB, relieve neuroinflammation	Therapeutic target	[58]
DCs	Exosomes	-	-	Improve myelination and reduce oxidative stress	Therapeutic target	[59]
NKs	Exosomes	miR-207	↑	Inhibit neuroinflammation	Therapeutic target	[60]
Bacteria-derived EVs
A. actinomycetemcomitans	OMV	exRNA	↑	Induce neuroinflammation	-	[68]
L. plantarum	EVs	-	-	Rescue the stress-induced decrease of BDNF, Sirt1 and MeCP2	Treatment	[69]
B. subtilis				Rescue stress-induced reduction of BDNF, Nt3, Nt4/5, and Sirt1
A. muciniphila
Blood-derived EVs
Serum	sEVs	Aldolase C	↑	-	Biomarkers	[22]
	Exosomes	miRNAs	↑/↓	Regulate neuronal functions involving MAPK, Wnt, and mTOR pathway	Biomarkers for the early diagnosis of depression	[75]
	EVs	miR-93-5p, miR-712-5p, miR-467b-3p, etc.	-	Modulate pro- or anti-inflammatory responses	Biomarkers	[76]
	Exosomes	miR-144-3p	↓	Involve synthesis, metabolism, and breakdown of fatty acids	Diagnostic biomarkers	[78]
	Exosomes	miR-144-5p	↓	Induce abnormal neurogenesis, neuronal apoptosis, altered synaptic plasticity, and neuroinflammation	Therapeutic target for MDD	[79]
	EVs	miR-450a-2-3p	↑	-	Diagnostic biomarkers	[80]
	EVs	miR-4433b-5p, miR-584-5p, miR-625-3p, miR-432-5p, miR-409-3p	↓	-	Diagnostic biomarkers	[81]
	EVs	miR-2277-3p miR-6813-3	↓	Involve glucocorticoid and gamma-aminobutyric acid receptor signaling	Diagnostic biomarkers for severity	[84]
				Involve dopaminergic neural pathway
	Exosomes	15 metabolites	↑	-	Diagnostic biomarkers for BD and MDD	[95]
Plasma	Exosomes	miR-16-5p, miR-129-5p, miR-363-3p, miR-92a-3p	↓	-	Diagnosis and treatment	[82]
	Exosomes	miR-335-5p	↑	Involve the synaptic synthesis and transport of many neurotransmitters	Biomarkers of diagnosis and treatment for ADT	[83]
		miR-1292-3p	↓
	Exosomes	miR-30a-5p	↑	Inhibit osteogenic differentiation	Biomarker and therapeutic target for osteoporosis caused by depression	[86]
	Exosomes	CXCL8	↑	Facilitate astrocyte-neuron communication	Therapeutic target for PTSD	[91]
	EVs	C3	↑	-	Diagnosis biomarkers for MDD	[92]
	Exosomes	sigma-1R	↑	Ameliorate inflammation response	Treatment	[94]
Blood/brain	Exosomes	miR-139-5p	↑	A negative regulator for neural stem cell proliferation and neuronal differentiation	Diagnosis and treatment	[85]
Blood	EVs	13 mRNAs	-	Involve synaptic function and myelination	Diagnosis biomarkers for PPD	[88]
Blood	Exosomes	SERPINF1	↓	A target of miR-186-5p	Biomarker for predicting MDD development	[89]

EVs: Extracellular vesicles; MDD: Major depressive disorder; PPD: Postpartum depression; sEVs: Small extracellular vesicles; OMVs: Outer membrane vesicles; DCs: Dendritic cells; NKs: natural killer cells; LFA-1: Lymphocyte function-associated antigen 1; ICAM-1: intercellular adhesion molecule 1; BDNF: Brain-derived neurotrophic factor; IL: Interleukin; TNF-α: Tumor necrosis factor α; ASCs: Adipose stem cells; NSCs: Neural stem cells; PLP: Proteolipid protein; CNP: 2’3’-cyclic-nucleotide-phosphodiesterase; MBP: Myelin basic protein; MOG: Myelin oligodendrocyte glycoprotein; ODEVs: Oligodendrocyte-derived extracellular vesicles; SIRT2: Sirtuin 2; FGF-2: Fibroblast growth factor-2; ApoD: Apolipoprotein-D; VEGF: Vascular endothelial growth factor; MSCs: Mesenchymal stromal cells; BMSCs: Bone marrow mesenchymal stem cells; BBB: Blood-brain barrier; A. actinomycetemcomitans: Aggregatibacter actinomycetemcomitans; L. plantarum: Lactobacillus plantarum; B. subtilis: Bacillus subtilis; A. muciniphila: Akkermansia muciniphila.