Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles

Table 3 Use of extracellular vesicles, derived from hypoxic mesenchymal stem cells, in regenerative medicine

Source of MSC	Culture	Hypoxic preconditions, O2%, percentage	Time of exposition	Major findings	Ref.
Human umbilical-cord	α-Mem deprived of FBS	1	72 h	Proangiogenic effects with an increase in UPAR, angiogenin, VEGF, IGF, Tie-2/TEK and IL-6 expression	[104]
	α-Mem deprived of FBS	1	72 h	Promoted angiogenesis in vitro and in vivo	[103]
	DMEM/high glucose media with 10% Exo depleted FBS and 1% penicillin/streptomycin	1	48 h	Enhanced of miRNA-126 exerting a pro-angiogenic effect in endothelial cells thereby activating Spred 1/Ras/Erk pathway	[117]
	α-Mem 10% EV free FBS	1	Not defined	EV encapsulated in a hyaluronic acid adhesive hydrogel have angiogenic properties and nerve regeneration effects after traumatic spinal cord injury	[107]
Olfactory mucosa	DMEM supplemented with 10% EV-depleted FBS	3	48 h	Promoted angiogenesis via miR-612 transfer	[112]
Adipose tissue	α-Mem 10% EV free serum	5	48 h	Promoted vessel formation in vitro. Enhanced angiogenesis, neovascularization and graft survival in vivo. Activation of VEGF/VEGF-R	[105,106]
	EV depleted standard medium	5	72 h	Promoted angiogenesis	[32]
	RPMI medium	1	72 h	Promoted angiogenesis, inhibition of apoptosis, immunomodulation, intracellular ATP recovery and reduction of ROS	[122]
	Microvascular endothelial cell growth medium 2 media deprived of FBS with supplement of 1× serum	1	24 h	Improved diabetic wound healing. Enhanced fibroblasts proliferation and migration activating PI3K/Akt pathway	[132]
	DMEM/F12 with 10% EV-free FBS	0–20 (5 cycles)	Hypoxia 60 min–reoxygenation 30 min	miRNA-224-5p in EV decreases TXNIP expression in cardiomyocytes and protects them from hypoxia mediated injury	[128]
Bone marrow	DMEM with low glucose containing inactivated 15% FBS	—	12 h	Increased of miRNA-21. Synaptic dysfunction restoration, inactivation of STAT3 and NF-kB, reduced plaque deposition and amyloid-β. Regulation of inflammatory responses in APP/PS1 mouse model	[114]
	DMEM with 10% FBS and 1% penicillin-streptomycin	5	6 d	High HMGB1 expression. Activation of JNK pathway and induction of HIF-1α/VEGF expression promoting angiogenesis	[111]
	Exosome-depleted fetal bovine serum	1	48 h	Increased exosomal levels of miRNA-216a-5p. Inhibition of TLR4/NF-κB and activation of PI3KAKT signaling pathway shifting microglial M1/M2 polarization	[115]
	α-Mem 10% exosomes-depleted FBS	2	48 h	Promoted angiogenesis	[118]
	Mesenchymal Stem Cells Medium (Sciencell) 5% exosomes-depleted FBS	1	48 h	Alleviate intervertebral disc degeneration by delivering miR-17-5p	[119]
	DMEM/F12 10% exosomes-depleted FBS	3	48 h	promote cartilage regeneration via the miR-205–5p/PTEN/AKT pathway	[120]
	DMEM/F12 10% exosomes-depleted FBS	5	48 h	EV improved chondrocyte proliferation and migration and suppressed chondrocyte apoptosis. miRNA-18-3P/JAK/STAT or miRNA-181c-5p/MAPK signaling pathway may be involved	[121]
	DMEM low glucose 10% platelet lysate	1	48 h	EV increase angiogenesis, reduced neuronal degeneration, brain atrophy and improved neurological recovery	[116]
Murine bone	α-Mem 10% Exo-removed FBS	0.5	24 h	Significant enrichment of miRNA-210. Promoted survival and recovery of cardiac functions. Also, reduced apoptosis and fibrosis and increased the mobilization of cardiac progenitor cells	[124]
	DMEM/F12 supplemented with 10% fetal bovine serum	1	72 h	Overexpression of miR-210 regulated PI3K/AKT and p53 signaling by targeting AIFM3 reducing apoptosis and tissue death after a myocardial infarction	[125]
	α-Mem 10% Exo-removed FBS	1	72 h	Overexpression of miR-125b-5p. Ability to modify the direction of exosomes to ischemic tissue	[126]

AIFM3: Apoptosis-inducing factor, mitochondria-associated 3; AKT: Protein kinase B (PKB), named derived from kinase encoded by oncogene in transforming retrovirus from thymoma cell line AKT-8 of stock A, strain k, AKR mouse; APP: Amyloid precursor protein; ATP: Adenosine triphosphate; DMEM: Dulbecco’s modified Eagle medium; Erk: Extracellular signal-regulated kinase; Exo: Exosomes; FBS: Fetal bovine serum; GM-CSF: Granulocyte macrophage colony-stimulating factor; HMGB1: High mobility group box 1 protein; IGF: Insulin-like growth factor; IL-6: Interleukin 6; JNK: Jun N-terminal kinase; MAPK: Mitogen-activated protein kinase; NF-B: Nuclear factor kappa B; P53: Tumor protein 53 (antioncogene); PI3K: Phosphatidylinositol 3-kinase; PS1: PreSenilin 1; RKCM: Growth medium stem cell; ROS: Reactive oxygen species; RPMI: Gibco Roswell Park Memorial Institute; Spred 1: Sprouty-related EVH1 domain-containing protein 1; STAT3: Signal transducer and activator of transcription 3; TEK: Tyrosine endothelial kinase; Tie-2: Tyrosine kinase receptor 2; TLR4: Toll-like receptor 4; TXNIP: Thioredoxin-interacting protein.; UPAR: Urokinase-type plasminogen activator receptor; VEGF: Vascular endothelial growth factor.