Update on the roles and applications of extracellular vesicles in depression

Figure 1 Risk factors for depression. Risk factors for depression include a family history of depression (approximately 35% of the risk is genetic), chronic diseases, social stress, unhealthy lifestyles, pregnancy and postpartum changes, substance use, sleep disorders, dysfunctional family functioning, and physical and psychological changes during adolescence. Created by Biorender.

Figure 2 Overview of different extracellular vesicles and exosomal contents. A: Biogenesis of different extracellular vesicles (EVs). (1) Exosomes (30-150 nm) are secreted via exocytosis of intraluminal vesicles, which are formed by the inward budding of the endosomal membrane. The fusion of multivesicular bodies (MVBs) with the plasma membrane facilitates their release into the extracellular space (blue arrows); (2) Microvesicles (100-1000 nm) originate from the outward budding and shedding of the plasma membrane; (3) Apoptotic bodies (500 nm to 5 μm) are released as cell fragments during the final stages of apoptotic cell death; and (4) The fusion of autophagosome with MVBs generates amphisomes. These amphisomes fuse with the plasma membrane to release autophagic EVs (green arrows); B: Exosomes contents. Exosomes contain a variety of comprise surface markers such as membrane transport/fusion proteins, tetraspanins, immune regulators, adhesion molecules, and lipid rafts. The package contents of exosomes encapsulate diverse biomolecules, such as proteins, nucleic acids, lipids, metabolites, and other cellular components. EVs: Extracellular vesicles; MVBs: Multivesicular bodies; ICAM-1: Intercellular adhesion molecule 1. Created by Biorender.

Figure 3 A summary of validated roles of extracellular vesicles derived from different sources in depression. (1) Astrocyte-derived extracellular vesicles (EVs) containing Apo-D act on neurons in the brain and play a neuroprotection role under oxidative stress; (2) Neuron-derived EVs containing miRNAs act on microglia; (3) Neuron-derived EVs containing miR-135a-3p, miR-6790-3p, and miR-11399 act on astrocytes to promote neuronal regeneration; (4) Neuron-derived EVs containing miR-9-5p promote M1 microglial polarization and neuronal damage; (5) Neurons stimulated by BDNF-derived EVs containing miR-132-5p, miR-218-5p, and miR-690 act on neurons and increase excitatory synapse clustering; (6) Microglia-derived EVs containing miR-146a-5p act on neurons and inhibit neurogenesis; (7) Oligodendrocyte-derived EVs containing sirtuin 2 act on neurons, promoting neurogenesis and synaptic plasticity; (8) Bone marrow mesenchymal stem cell-derived EVs containing miR-26a act on neurons and promote neuronal proliferation; (9) NK EVs containing miR-207 act on astrocytes and reduce neuroinflammation; (10) Neural stem cell-derived EVs containing miR-16-5p inhibit neuron apoptosis; (11) Aggregatibacter actinomycetemcomitans-derived EVs containing exRNA act on microglia and promote neuroinflammation; (12) Serum-derived EVs act on neurons, promoting neuronal proliferation and neurogenesis; (13) Astrocyte-derived EVs in plasma act on neurons and promote neuroinflammation; (14) EVs derived from blood act on neuronal stem cells and promote neuronal differentiation; and (15) Brain-derived EVs transfer to the periphery through the blood-brain barrier, with abnormal expression of certain proteins and miRNAs observed in blood. BDNF: Brain-derived neurotrophic factor; IL: Interleukin; TNF-α: Tumor necrosis factor α; BMSCs: Bone marrow mesenchymal stem cells; NSCs: Neural stem cells; SIRT2: Sirtuin 2; Aa: Aggregatibacter actinomycetemcomitans. Created by Biorender.