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. 2020 May;45(6):1050-1058.
doi: 10.1038/s41386-020-0622-2. Epub 2020 Jan 27.

Exosomes from patients with major depression cause depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis

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Exosomes from patients with major depression cause depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis

Ze-Xu Wei et al. Neuropsychopharmacology. 2020 May.

Abstract

Exosomal microRNAs (miRNAs) have been suggested to participate in the pathogenesis of neuropsychiatric diseases, but their role in major depressive disorder (MDD) is unknown. We performed a genome-wide miRNA expression profiling of blood-derived exosomes from MDD patients and control subjects and revealed the top differentially expressed exosomal miRNA, i.e. hsa-miR-139-5p (upregulation), had good performance to differentiate between MDD patients and controls. Tail vein injection of blood exosomes isolated from MDD patients into normal mice caused their depressive-like behaviors as determined by the forced swimming, tail suspension, and novelty suppressed feeding tests, and injection of blood exosomes isolated from healthy volunteers into unpredictable mild stress (CUMS)-treated mice alleviated their depressive-like behaviors. CUMS mice also showed significantly increased blood and brain levels of exosomal miR-139-5p. Furthermore, the depressive-like behaviors in CUMS-treated mice were rescued by intranasal injection of miR-139-5p antagomir, suggesting that increased exosomal miR-139-5p levels may mediate stress-induced depression-like behavior in mice. Both exosome treatment and miR-139-5p antagomir treatment increased hippocampal neurogenesis in the CUMS-treated mice, and treatment of exosome from MDD patients decreased hippocampal neurogenesis in the normal mice. The role of miR-139-5p in neurogenesis was validated by in vitro experiments, demonstrating that miR-139-5p is a negative regulator for neural stem cell proliferation and neuronal differentiation. Our findings together suggest that exosomes from patients with major depression caused depressive-like behaviors in mice with involvement of miR-139-5p-regulated neurogenesis. Therefore, exosomal miRNAs are promising targets for the diagnosis and treatment of MDD.

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Figures

Fig. 1
Fig. 1. Blood exosomal miRNAs as biomarkers for major depressive disorder (MDD).
a Heatmap of differentially expressed blood exosomal miRNAs between MDD patients and healthy control subjects. b qRT-PCR validation of has-miR-139-5p expression in the blood exosomes of MDD patients; HC healthy controls, SZ schizophrenia. ROC curves were used to evaluate the accuracy of has-miR-139-5p (c), a cluster of 25 miRNAs (d), and a cluster of ten miRNAs (e) for the diagnosis of MDD; AUC area under the curve. f Dendrogram showing miRNA coexpression modules defined in 79 samples. g Pearson’s correlation coefficient between disease status, age, gender, the Hamilton Depression Rating Scale (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS), and module eigengene. h Log2-transformed fold change distribution of miRNAs in the modules black, blue, brown, magenta, pink, and red.
Fig. 2
Fig. 2. Treatment of exosomes isolated from major depressive disorder (MDD) patients leads to depressive-like behaviors in mice.
Infusion of exosomes isolated from MDD patients into normal mice caused their depressive-like behaviors as assessed by tail suspension test (a), forced swimming test (b), and novelty suppressed feeding test (c). d Traveling distance of different groups of mice in the open-field test. Confocal photomicrographs of DCX-immunostained immature neurons (e) and BrdU/NeuN double-immunostained newborn mature neurons (g) in the dentate gyrus of mice under various treatments. Quantification of DCX-positive cells (f) and newborn mature neurons (h) in the dentate gyrus of mice under various treatments, n = 5. t test. *p < 0.05, **p < 0.01.
Fig. 3
Fig. 3. Exosome administration lessens depressive-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS).
CUMS led to depression-like behaviors in mice and administration of blood exosomes form healthy humans reversed the phenotypes as assessed by tail suspension test (a), forced swimming test (b), and novelty suppressed feeding test (c). d Traveling distance of different groups of mice in the open-field test. Effects of exosome treatment on the changes of total antioxidant capacity (T-AOC) (e), glutathione peroxidase (GSH-PX) (f) and malondialdehyde (MDA) (g) in the serum of CUMS mice. h Confocal photomicrographs of DCX-immunostained immature neurons in the subgranular zone of the dentate gyrus of mice under various treatments. i Quantification of DCX-positive cells on the subgranular zone of mice with various treatments, n = 4. j Heatmap of the 274 significantly differentially expressed (DE) proteins in the hippocampus of control and CUMS mice. k Heatmap of the 201 significantly DE proteins in the hippocampus of saline- and exosome-treated CUMS mice. One-way ANOVA with Tukey’s post hoc test. *p < 0.05, **p < 0.01, ***p < 0.001. Data are expressed as mean ± SEM.
Fig. 4
Fig. 4. Downregulation of exosomal miR-139-5p alleviates depressive-like behaviors in CUMS mice.
a Bar graphs showing the quantification of miR-139-5p levels in the blood exosome of CUMS mice and control mice. b Bar graphs showing the quantification of whole-brain miR-139-5p levels in the CUMS mice and control mice. c Bar graphs showing the quantification of miR-139-5p levels in the brain exosome of CUMS mice and control mice. d Brain exosomal miR-139-5p expression under various treatments in the mice. Intranasal administration of miR-139-5p antagomir reversed depressive-like behaviors in CUMS mice as assessed by tail suspension test (e), forced swimming test (f) and novelty suppressed feeding test (g). h Traveling distance of different groups of mice in the open-field test. Confocal photomicrographs of DCX-immunostained immature neurons (i) and BrdU/NeuN double-immunostained newborn mature neurons (k) in the dentate gyrus of control (I) and CUMS (II) mice treated with vehicle, and control (III) and CUMS (IV) mice treated with miR-139-5p antagomir. Quantification of DCX-positive cells (j) and newborn mature neurons (l) in the dentate gyrus of mice under various treatments, n = 5. ac t test, dh, j, l one-way ANOVA with Tukey’s post hoc test. *p < 0.05, **p < 0.01, ***p < 0.001. Data are expressed as mean ± SEM. NC negative control.
Fig. 5
Fig. 5. miR-139-5p is a negative regulator for neuronal differentiation.
a Representative confocal pictures (×20, left panel) and quantification (right panel) of MAP2 and GFAP-immunostained cells after miR-139-5p and miR-control treatments in the neural stem cells (NSCs). b Representative ICC confocal pictures (×20) (left panel) and quantification (right panel) of MAP2 and GFAP-immunostained cells after anti-miR-139-5p and anti-miR-control treatments in the NSCs. c Western blot analysis showing downregulation of MAP2 protein expression and upregulation of GFAP protein expression after miR-139-5p treatment in the NSCs. d Western blot analysis showing upregulation of MAP2 protein expression and downregulation of GFAP protein expression after anti-miR-139-5p treatment in the NSCs. e Proposed model illustrating role of exosome-derived miR-139-5p in depressive-like behaviors during stress. a, b n = 15; c, d n = 3. t test, *p < 0.05, **p < 0.01, ***p < 0.001. Data are expressed as mean ± SEM.

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