Table 1.

Summary of EVs used in periodontal tissue regeneration.

Cell sourceEVs typeIsolation protocolCargoesEffectsMechanismsRef.
BMSCEVsGradient ultracentrifugationBgnPromote osteoblast proliferation, migration, differentiation, and mineralizationPI3K/AKT81
M2
Macrophage
ExosDifferential centrifugationLet-7f-5pPromote cementoblast mineralizationDownregulation of Ckip-1 by Let-7f-5p activates mitochondrial biogenesis118
MSCEVsDifferential centrifugationmiR-612Promote ECs migration, proliferation and angiogenesismiR-612/TP53/HIF-1α121
BMSCEVsPolymer precipitation, centrifugation techniquesBMP2Induce osteoinduction and bone regenerationPhosphorylation of Smad 1/5/895
DPSCAbsDifferential centrifugationTUFM,
TFEB
Promote ECs proliferation and angiogenesisThe TFEB-induced autophagy-lysosome pathway125
BMSCEVsPolymer precipitation, centrifugation techniquesOPGPromote PDLSCs proliferation, migration and differentiation;
Inhibit osteoclast activity; promote M2 macrophage polarization
OPG/RANKL/RANK84
PDLSCExosDifferential centrifugationmiR-31-5pInhibit osteoclast formation and reduce bone destructionmiR-31-5p/eNOS87
GMSCExosImmunoprecipitation, ultracentrifugationmiR-1260b/CD73Promote M2 macrophage polarization and enhance wound healing;
Promote osteogenesis and inhibit bone loss
Wnt5a/JNK/RANKL53
DPSCEVsUltracentrifugationmiR-1246Promote osteogenesisUpregulation of miR-1246107
SCAPEVsUltracentrifugation, differential centrifugationmiR-935Promote osteoblast differentiation of PDLSCs; inhibit inflammation and bone resorptionUpregulation of miR-935109
SHEDExosUltracentrifugation, differential centrifugationβ-catenin, Wnt3a, BMP2Promote osteoblast differentiation of PDLSCsWnt/β-catenin;
BMP/Smad (the phosphorylation of Smad 1/5/8)
98
BMSCEVsPolymer precipitation,ultrafiltrationmiR-424Promote bone formationPhosphorylation of Smad 1/5/896
BMSCExos UltracentrifugationDPT-C, miR-26aPromote osteogenesis, proliferation and migration of BMSCsmTOR pathway/Wnt/autophagy91
BMSCAbsDifferential centrifugationmiR-223-3PInhibit osteoclast activity and alleviate bone destructionTarget Itgb164
BMSC,
ASC
ExosGradient ultracentrifugationlet-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5pPromote osteoblast differentiation of BMSCsTargeted Acvr2b/Acvr1 and regulate the balance of Bmpr2/Acvr2b for Bmpr-elicited Smad1/5/9 phosphorylation97
BMSCExos UltracentrifugationmiR-130aPromote ECs migrationPTEN/AKT; Wnt/β-catenin NF-κB/AKT124
SHEDEVsDifferential centrifugationChemotactic Factors
(TGF-β1, IGF-1, FGF-2, PDGF-BB)
Promote migration of BMSCsChemotactic effect129
DPSCEVsDifferential centrifugationmiR-758-5pPromote osteoblast differentiation of PDLSCsmiR-758-5p/LMBR1/BMP2/494
PDLSCExosUltracentrifugationmiR-17-5pIncrease VEGFA and promote tube formation of ECsDownregulation of miR-17-5p122
DPSCEVsUltracentrifugationmiR-378aPromote ECs migration, proliferation, tube formation and angiogenesismiR-378a/Sufu/Hedgehog/Gli1123
Cell sourceEVs typeIsolation protocolCargoesEffectsMechanismsRef.
BMSCEVsGradient ultracentrifugationBgnPromote osteoblast proliferation, migration, differentiation, and mineralizationPI3K/AKT81
M2
Macrophage
ExosDifferential centrifugationLet-7f-5pPromote cementoblast mineralizationDownregulation of Ckip-1 by Let-7f-5p activates mitochondrial biogenesis118
MSCEVsDifferential centrifugationmiR-612Promote ECs migration, proliferation and angiogenesismiR-612/TP53/HIF-1α121
BMSCEVsPolymer precipitation, centrifugation techniquesBMP2Induce osteoinduction and bone regenerationPhosphorylation of Smad 1/5/895
DPSCAbsDifferential centrifugationTUFM,
TFEB
Promote ECs proliferation and angiogenesisThe TFEB-induced autophagy-lysosome pathway125
BMSCEVsPolymer precipitation, centrifugation techniquesOPGPromote PDLSCs proliferation, migration and differentiation;
Inhibit osteoclast activity; promote M2 macrophage polarization
OPG/RANKL/RANK84
PDLSCExosDifferential centrifugationmiR-31-5pInhibit osteoclast formation and reduce bone destructionmiR-31-5p/eNOS87
GMSCExosImmunoprecipitation, ultracentrifugationmiR-1260b/CD73Promote M2 macrophage polarization and enhance wound healing;
Promote osteogenesis and inhibit bone loss
Wnt5a/JNK/RANKL53
DPSCEVsUltracentrifugationmiR-1246Promote osteogenesisUpregulation of miR-1246107
SCAPEVsUltracentrifugation, differential centrifugationmiR-935Promote osteoblast differentiation of PDLSCs; inhibit inflammation and bone resorptionUpregulation of miR-935109
SHEDExosUltracentrifugation, differential centrifugationβ-catenin, Wnt3a, BMP2Promote osteoblast differentiation of PDLSCsWnt/β-catenin;
BMP/Smad (the phosphorylation of Smad 1/5/8)
98
BMSCEVsPolymer precipitation,ultrafiltrationmiR-424Promote bone formationPhosphorylation of Smad 1/5/896
BMSCExos UltracentrifugationDPT-C, miR-26aPromote osteogenesis, proliferation and migration of BMSCsmTOR pathway/Wnt/autophagy91
BMSCAbsDifferential centrifugationmiR-223-3PInhibit osteoclast activity and alleviate bone destructionTarget Itgb164
BMSC,
ASC
ExosGradient ultracentrifugationlet-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5pPromote osteoblast differentiation of BMSCsTargeted Acvr2b/Acvr1 and regulate the balance of Bmpr2/Acvr2b for Bmpr-elicited Smad1/5/9 phosphorylation97
BMSCExos UltracentrifugationmiR-130aPromote ECs migrationPTEN/AKT; Wnt/β-catenin NF-κB/AKT124
SHEDEVsDifferential centrifugationChemotactic Factors
(TGF-β1, IGF-1, FGF-2, PDGF-BB)
Promote migration of BMSCsChemotactic effect129
DPSCEVsDifferential centrifugationmiR-758-5pPromote osteoblast differentiation of PDLSCsmiR-758-5p/LMBR1/BMP2/494
PDLSCExosUltracentrifugationmiR-17-5pIncrease VEGFA and promote tube formation of ECsDownregulation of miR-17-5p122
DPSCEVsUltracentrifugationmiR-378aPromote ECs migration, proliferation, tube formation and angiogenesismiR-378a/Sufu/Hedgehog/Gli1123

Abbreviations: ABs, apoptotic bodies; AKT, protein kinase B; ASC(ADSC), adipose-derived stem cells; BMP2, bone morphogenetic protein 2; BMSC, bone mesenchymal stem cells; DPSC, dental pulp stem cells; ECs, endothelial cells; EVs, extracellular vesicles; Exos, exosomes; GMSC, gingival mesenchymal stem cells; HIF-1α, hypoxia-inducible factor 1-alpha; JNK, c-Jun N-terminal kinaseMSC, mesenchymal stem cells; OPG, osteoprotegerin; PDLSC, periodontal ligament stem cells; PI3K, phosphatidylinositide 3-kinase; RANK, receptor activator of nuclear factor κ; RANKL, receptor activator of nuclear factor κB ligand; SCAP, stem cells from the apical papilla; SHED, stem cells from human exfoliated deciduous teeth; TUFM, Tu translation elongation factor; VEGFA, vascular endothelial growth factor A; Wnt3a, wingless protein 3a.

Table 1.

Summary of EVs used in periodontal tissue regeneration.

Cell sourceEVs typeIsolation protocolCargoesEffectsMechanismsRef.
BMSCEVsGradient ultracentrifugationBgnPromote osteoblast proliferation, migration, differentiation, and mineralizationPI3K/AKT81
M2
Macrophage
ExosDifferential centrifugationLet-7f-5pPromote cementoblast mineralizationDownregulation of Ckip-1 by Let-7f-5p activates mitochondrial biogenesis118
MSCEVsDifferential centrifugationmiR-612Promote ECs migration, proliferation and angiogenesismiR-612/TP53/HIF-1α121
BMSCEVsPolymer precipitation, centrifugation techniquesBMP2Induce osteoinduction and bone regenerationPhosphorylation of Smad 1/5/895
DPSCAbsDifferential centrifugationTUFM,
TFEB
Promote ECs proliferation and angiogenesisThe TFEB-induced autophagy-lysosome pathway125
BMSCEVsPolymer precipitation, centrifugation techniquesOPGPromote PDLSCs proliferation, migration and differentiation;
Inhibit osteoclast activity; promote M2 macrophage polarization
OPG/RANKL/RANK84
PDLSCExosDifferential centrifugationmiR-31-5pInhibit osteoclast formation and reduce bone destructionmiR-31-5p/eNOS87
GMSCExosImmunoprecipitation, ultracentrifugationmiR-1260b/CD73Promote M2 macrophage polarization and enhance wound healing;
Promote osteogenesis and inhibit bone loss
Wnt5a/JNK/RANKL53
DPSCEVsUltracentrifugationmiR-1246Promote osteogenesisUpregulation of miR-1246107
SCAPEVsUltracentrifugation, differential centrifugationmiR-935Promote osteoblast differentiation of PDLSCs; inhibit inflammation and bone resorptionUpregulation of miR-935109
SHEDExosUltracentrifugation, differential centrifugationβ-catenin, Wnt3a, BMP2Promote osteoblast differentiation of PDLSCsWnt/β-catenin;
BMP/Smad (the phosphorylation of Smad 1/5/8)
98
BMSCEVsPolymer precipitation,ultrafiltrationmiR-424Promote bone formationPhosphorylation of Smad 1/5/896
BMSCExos UltracentrifugationDPT-C, miR-26aPromote osteogenesis, proliferation and migration of BMSCsmTOR pathway/Wnt/autophagy91
BMSCAbsDifferential centrifugationmiR-223-3PInhibit osteoclast activity and alleviate bone destructionTarget Itgb164
BMSC,
ASC
ExosGradient ultracentrifugationlet-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5pPromote osteoblast differentiation of BMSCsTargeted Acvr2b/Acvr1 and regulate the balance of Bmpr2/Acvr2b for Bmpr-elicited Smad1/5/9 phosphorylation97
BMSCExos UltracentrifugationmiR-130aPromote ECs migrationPTEN/AKT; Wnt/β-catenin NF-κB/AKT124
SHEDEVsDifferential centrifugationChemotactic Factors
(TGF-β1, IGF-1, FGF-2, PDGF-BB)
Promote migration of BMSCsChemotactic effect129
DPSCEVsDifferential centrifugationmiR-758-5pPromote osteoblast differentiation of PDLSCsmiR-758-5p/LMBR1/BMP2/494
PDLSCExosUltracentrifugationmiR-17-5pIncrease VEGFA and promote tube formation of ECsDownregulation of miR-17-5p122
DPSCEVsUltracentrifugationmiR-378aPromote ECs migration, proliferation, tube formation and angiogenesismiR-378a/Sufu/Hedgehog/Gli1123
Cell sourceEVs typeIsolation protocolCargoesEffectsMechanismsRef.
BMSCEVsGradient ultracentrifugationBgnPromote osteoblast proliferation, migration, differentiation, and mineralizationPI3K/AKT81
M2
Macrophage
ExosDifferential centrifugationLet-7f-5pPromote cementoblast mineralizationDownregulation of Ckip-1 by Let-7f-5p activates mitochondrial biogenesis118
MSCEVsDifferential centrifugationmiR-612Promote ECs migration, proliferation and angiogenesismiR-612/TP53/HIF-1α121
BMSCEVsPolymer precipitation, centrifugation techniquesBMP2Induce osteoinduction and bone regenerationPhosphorylation of Smad 1/5/895
DPSCAbsDifferential centrifugationTUFM,
TFEB
Promote ECs proliferation and angiogenesisThe TFEB-induced autophagy-lysosome pathway125
BMSCEVsPolymer precipitation, centrifugation techniquesOPGPromote PDLSCs proliferation, migration and differentiation;
Inhibit osteoclast activity; promote M2 macrophage polarization
OPG/RANKL/RANK84
PDLSCExosDifferential centrifugationmiR-31-5pInhibit osteoclast formation and reduce bone destructionmiR-31-5p/eNOS87
GMSCExosImmunoprecipitation, ultracentrifugationmiR-1260b/CD73Promote M2 macrophage polarization and enhance wound healing;
Promote osteogenesis and inhibit bone loss
Wnt5a/JNK/RANKL53
DPSCEVsUltracentrifugationmiR-1246Promote osteogenesisUpregulation of miR-1246107
SCAPEVsUltracentrifugation, differential centrifugationmiR-935Promote osteoblast differentiation of PDLSCs; inhibit inflammation and bone resorptionUpregulation of miR-935109
SHEDExosUltracentrifugation, differential centrifugationβ-catenin, Wnt3a, BMP2Promote osteoblast differentiation of PDLSCsWnt/β-catenin;
BMP/Smad (the phosphorylation of Smad 1/5/8)
98
BMSCEVsPolymer precipitation,ultrafiltrationmiR-424Promote bone formationPhosphorylation of Smad 1/5/896
BMSCExos UltracentrifugationDPT-C, miR-26aPromote osteogenesis, proliferation and migration of BMSCsmTOR pathway/Wnt/autophagy91
BMSCAbsDifferential centrifugationmiR-223-3PInhibit osteoclast activity and alleviate bone destructionTarget Itgb164
BMSC,
ASC
ExosGradient ultracentrifugationlet-7a-5p, let-7c-5p, miR-328a-5p, miR-31a-5pPromote osteoblast differentiation of BMSCsTargeted Acvr2b/Acvr1 and regulate the balance of Bmpr2/Acvr2b for Bmpr-elicited Smad1/5/9 phosphorylation97
BMSCExos UltracentrifugationmiR-130aPromote ECs migrationPTEN/AKT; Wnt/β-catenin NF-κB/AKT124
SHEDEVsDifferential centrifugationChemotactic Factors
(TGF-β1, IGF-1, FGF-2, PDGF-BB)
Promote migration of BMSCsChemotactic effect129
DPSCEVsDifferential centrifugationmiR-758-5pPromote osteoblast differentiation of PDLSCsmiR-758-5p/LMBR1/BMP2/494
PDLSCExosUltracentrifugationmiR-17-5pIncrease VEGFA and promote tube formation of ECsDownregulation of miR-17-5p122
DPSCEVsUltracentrifugationmiR-378aPromote ECs migration, proliferation, tube formation and angiogenesismiR-378a/Sufu/Hedgehog/Gli1123

Abbreviations: ABs, apoptotic bodies; AKT, protein kinase B; ASC(ADSC), adipose-derived stem cells; BMP2, bone morphogenetic protein 2; BMSC, bone mesenchymal stem cells; DPSC, dental pulp stem cells; ECs, endothelial cells; EVs, extracellular vesicles; Exos, exosomes; GMSC, gingival mesenchymal stem cells; HIF-1α, hypoxia-inducible factor 1-alpha; JNK, c-Jun N-terminal kinaseMSC, mesenchymal stem cells; OPG, osteoprotegerin; PDLSC, periodontal ligament stem cells; PI3K, phosphatidylinositide 3-kinase; RANK, receptor activator of nuclear factor κ; RANKL, receptor activator of nuclear factor κB ligand; SCAP, stem cells from the apical papilla; SHED, stem cells from human exfoliated deciduous teeth; TUFM, Tu translation elongation factor; VEGFA, vascular endothelial growth factor A; Wnt3a, wingless protein 3a.

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