Table 1.

The application of stem cell-derived extracellular vesicle in neurodegenerative diseases

Disease	Origin and type of EVs	Route of administration	Outcomes	Ref
Alzheimer’s disease	Bone marrow mesenchymal stem cells/extracellular vesicles	Not reported	Decrease extracellular Aβ oligomer level through: - Endocytic and degradation by MSCs - Secretion EVs containing the catalase - Release of anti-inflammatory cytokines (IL-6, IL-10, and VEGF)	[194]
	Bone marrow mesenchymal stem cells/extracellular vesicles	Intracerebral injection	Prevent Aβ plaque formation and reduce dystrophic neurons: - Increase plaque phagocytosis by microglial cells - Proteolysis of Aβ plaques by neprilysin	[146]
	Human adipose tissue-derived mesenchymal stem cells/extracellular vesicles	Not reported	Proteolysis of Aβ plaques by neprilysin	[193]
	Mesenchymal stem cells/exosomes	Stereotactic administration	Promote neurogenesis and cognitive function recovery	[136]
	Cytokine (TNFα and INFγ) preconditioned mesenchymal stem cells/extracellular vesicles	Intranasal administration	Improve in dendritic spine density through: - Downregulation IL-6 and IL-1β and upregulation IL-10 - Polarization microglia toward an anti-inflammatory phenotype	[147]
	Wharton’s jelly mesenchymal stem cells/extracellular vesicles	Not reported	Increases the resistance of hippocampal neurons to damage caused by Aβ through: - Regulating the function of astrocytes - Decreasing ROS production	[195]
	Hypoxia-preconditioned mesenchymal stem cells/extracellular vesicles	Systemic administration	Reduced intracellular and extracellular deposition of Aβ oligomers Ameliorates learning and memory deficits through: - reduce pro-inflammatory cytokines (IL-1β and TNF-α) and vice versa, increase inflammatory cytokines (IL-4 and IL-10) - decrease the activity of STAT3 and NF-κB	[196]
	Neural stem cells/extracellular vesicles	Stereotactic administration	Improve cognitive dysfunction through: - improve mitochondrial function, SIRT1 activation, synaptic activity - reduction in inflammatory response	[148]
	Heat-shock neural stem cells/exosomes	Not reported	Improves cognitive and motor function	[153]
Parkinson’s disease	Human exfoliated deciduous teeth stem cells (SHEDs)/exosomes	Not reported	Inhibition the apoptosis-induced by (6-OHDA) in human dopaminergic neurons	[206]
	Human exfoliated deciduous teeth stem cells (SHEDs)/extracellular vesicles	Intranasal administration	Improve motor symptoms through: - normalizes tyrosine hydroxylase expression in the substantia nigra and striatum of the (6-OHDA)-treated rats	[152]
	Mesenchymal stem cells/exosomes	Tail vein injections	Regulate neurite outgrowth by transfer of the miR-133b	[212]
	Mesenchymal stem cells/exosomes	Not reported	Stimulation of oligodendrogenesis and improving neuronal function	[165]
Multiple sclerosis	Periodontal ligament stem cells/exosomes	Intravenous injection	Remyelination in the spinal cord through: - increase of anti-inflammatory cytokines including IL-10 and contrary to decrease the level of pro-inflammatory cytokines	[225]
	Placenta-derived MSCs/extracellular vesicles	Subcutaneous injections	Improving motor function and induce myelin regeneration through: - modulation immune system and induce the regulatory T cell differentiation by its growth factors cargo (HGF and VEGF)	[144]
	Mesenchymal stem cells/extracellular vesicles	Not reported	Induce peripheral tolerance, active the apoptotic signaling in the self-reactive lymphocyte and induce the differentiation of regulatory T cells through: - secretion anti-inflammatory cytokines (IL-10 and TGF-β) -expression of regulatory molecules (PD-L1 and TGF-β) on the MV	[228]
	Mesenchymal stem cells/exosomes	Tail vein injections	Attenuate inflammation and demyelination of the CNS through: - altering the polarization of microglia toward a M2 phenotype	[231]
	Adipose tissue-derived mesenchymal stem cells/nanovesicles	Intravenous injections	Reducing demyelination in the spinal cord through: - decreased activity CNS immune cells including microglial and T cell	[232]
	Human adipose tissue-derived mesenchymal stem cells/extracellular vesicles	Intravenous injections	Attenuates induced-EAE through: - diminishing proliferative potency of T cells - leukocyte infiltration - demyelination on a chronic model of MS	[134]
Stroke	Bone marrow mesenchymal stem cells/exosomes	Intravenous injection	Ameliorates functional recovery and increase axonal density and synaptophysin-positive areas through: - improves neurite remodeling, neurogenesis, and angiogenesis	[162]
	Bone marrow mesenchymal stem cells/exosome	Intravenous injection	Stimulate long-term neuroprotection, promote neuroregeneration and neurological recovery through: - modulate peripheral post-stroke immune responses	[139]
	Adipose mesenchymal stem cells/extracellular vesicles	Intravenous injection	Improve functional recovery through: - fiber tract integrity, axonal sprouting and white matter repair	[154]
	Human neural stem cells/extracellular vesicles	Intravenous injection	Improving behavior and mobility through: - decrease intracranial hemorrhage in ischemic lesions - elimination in cerebral lesion volume and decreased brain swelling and reduce edema	[163]
	Human neural stem cells/extracellular vesicles	Tail vein injection	Ameliorate tissue and functional recovery and episodic memory formation through: - changing the systemic immune response	[132]
	Neural stem cell and human induced pluripotent stem cell-derived cardiomyocyte (iCM)/exosome	Intravenous injection	Reduced infarct volumes and induce neuroprotection through: - preservation the function of astrocyte	[141]
	Mesenchymal stem cells/exosome	Intravenous injection	Improving behavior function through: - neurogenesis and angiogenesis mediated by miRNA-184 and miRNA-210	[142]