Review
Copyright ©The Author(s) 2023.
World J Stem Cells. Mar 26, 2023; 15(3): 31-51
Published online Mar 26, 2023. doi: 10.4252/wjsc.v15.i3.31
Table 1 Characteristics of different types of dental stem cells
Cell types
Markers
Multidirectional differentiations
Cell surface markers
Embryonic stem cell markers
Nerual markers
DPSCsCD13, CD29, CD44, CD59, CD73, CD90, CD105, CD146, STRO-1[7], CD81, CD49f[140], CD40, CD120a, CD261, CD262, CD264, CD266, CD121a, CD130, CD213a1, CD217, CDw210b[141]OCT-4, Nanog[142], SSEA-1, SEEA-4[140], SOX-2[143]βIII-tubulin, NFM, Nestin, CNPase[144], S100, CD271[17]Osteogenic, Odontogenic[145], Dentinogeni, Chondrogenic, Neurogenic, Myogenic, Adipogenic[13], Hepatogenic[146]
PDLSCsCD13, CD29, CD44, CD49, CD73, CD90, CD105, CD146, CD166, CD271[147], CD10[7], STRO-1[148]SSEA-1, SSEA-3, SSEA-4, TRA-1-60, TRA-1-81, OCT-4, Nanog, SOX-2, REX1, and ALP[149]Nestin, OCT-4, SSEA-4[9] CD271, SOX-10[147], SOX-2[149]Osteogenic, Cementogenic, Adipogenic, Chondrogenic, Neurogenic[13], Hepatogenic[149], Cardiac myogenic, Endothelial-like, Islet-like, Retinal ganglion-like[147]
SCAPCD13, CD24, CD29, CD44, CD49, CD51, CD56, CD61, CD73, CD90, CD105, CD106, CD146, CD166, STRO-1, NOTCH-3[150], CD81, CD49f[151]OCT-4, Nanog, SOX2[143], CD49f[151]βIII-tubulin, NFM, Nestin, CNPase[144], SOX-2[143], Vimentin, Survivin[150]Osteogenic, Dentinogenic, Adipogenic[15], Neurogenic[13], Chondrogenic, Hepatogenic[150]
SHEDCD29, CD73, CD90, CD166[13], STRO-1, CD44[145], CD105[152], NOTCH-1, CD10, CD13, CD34, CD106, CD146, CD166, CD271[102]OCT-4, Nanog, SSEA-3[153], SSEA-4[152], NOTCH-1, OCT-4, SOX-2[102]βIII-tubulin, NFM, Nestin, CNPase, GAD, NeuN, GFAP[154], CD271, Vimentin, OCT-4, PAX-6, NSE, MAP-2, PSA-NCAM, TH[102]Osteogenic, Odontogenic[145], Dentinogenic, Chondrogenic, Neurogenic, Myogenic, Adipogenic[13], Hepatogenic[155]
DFPCsCD13, CD29, CD59, CD90[7], CD105, CD146[142], CD44, CD73, NOTCH-1, STRO-1[156]OCT-4, Nanog[142], NOTCH-1, SOX-2[156]OCT-4, SOX2[9], Nestin, SOX-2[156]Osteogenic, Cementogenic, Odontogenic, Adipogenic, Chondrogenic[13], Hepatogenic[146]
GMSCsCD13, CD29, CD44, CD73, CD90, CD105, CD146, STRO-1[16]SSEA-4[16], OCT-4, Nanog[157]Nestin, SOX10[16], βIII-tubulin, NFM, CNPase[144]Osteogenic, Adipogenic, Chondrogenic, Neurogenic, Endothelial-like, Odontogenic[16], Myogenic[158]
Table 2 Dental stem cell-based clinical trials from published articles
Ref.
Registration ID
Conditions/diseases
Study design
Cell source
Administration route
Interventions
Follow-up period
Outcomes
Test group
Control group
Xuan et al[28], 2018NCT01814436Pulp necrosisRCTAutologous deciduous pulpImplanted into injured teethSHED (n = 26)Traditional apexification treatment (n = 10)12 mo; 24 moDental pulp tissue regeneration; no adverse events observed; the length of the root (↑); the width of the apical foramen (↓)
Nakashima et al[35], 2022NoneIrreversible pulpitisCase seriesAutologous dental pulpTransplanted into the root canalDPSCs + Gelatin sponge + G-CSF (n = 5)None1, 2, 4, 12, 24, 28, 32 wkPulp sensibility (↑); MRI examination showed similar SI between test teeth and untreated controls
Nakashima et al[37], 2017NoneIrreversible pulpitisCase seriesAutologous dental pulpTransplanted into the root canalDPSCs + Gelatin sponge + G-CSF (n = 2)None1, 4, 12, 24, and 48 wkMRI examination showed similar SI between test teeth and untreated controls; mineralized tissue deposition (↑)
Meza et al[36], 2019NoneIrreversible pulpitisA case reportAutologous inflamed dental pulpTransplanted into the root canalDPSCs + L-PRF (n = 1)None6 mo; 3 yearDelayed response to the cold test; positive response to electric pulp testing; dentin bridge formation
Shiehzadeh et al[38], 2014NonePeriapical lesionsCase seriesCase 1 and case 3: Autologous apical papilla; case 2: Deciduous pulpCase 1 and Case 3: Injected from root apex to cavity; case 2: Injected into the defect via a surgical approachCase 1 and Case 3: SCAP + PEG-PLGA scaffold (n = 2); case 2: SHED + PEG-PLGA scaffold (n = 1)NoneCase 1: 30 d, 3 mo, 1 year; 2 year; case 2: 3, 6, 18 mo; case 3: 3, 6, 12, 24 moDeveloped mature apices; periapical tissue healing (↑)
Prasad et al[39], 2017NonePeriapical lesionsCase seriesAllogeneic deciduous pulpTransplanted into the root canalSHED + Bioglass (n = 2)None7, 30, 90, 180, 365 dClosure of open apex; periapical tissue healing; positive response to electric pulp testing and cold testing
Prasad et al[40], 2019NonePeriapical lesionsA case reportAllogeneic deciduous pulpTransplanted into the root canal and periapical areaSHED + Bioglass (n = 1)None2 wk; 4, 12, 24 moPeriapical tissue healing; positive response to electric pulp testing
Ferrarotti et al[41], 2018NCT03386877Periodontal intrabony defectsRCTAutologous dental pulpImplanted into bone defect sites consisted of MISTPulp micrografts + Collagen sponge (n = 15)Collagen sponge (n = 14)6 and 12 moPD (↓); CAL (↓); bone defect fill (↑); residual PD < 5 mm and CAL gain ≥ 4 mm (↑)
Sánchez et al[42], 2020ISRCTN13093912Periodontal intrabony defectsCCTAutologous periodontal ligamentImplanted into bone defect sites via surgical approachPDLSCs + β-TCP (n = 9)β-TCP (n = 10)1, 3, 6, 9, 12 moCAL (-); PPD (-)
Feng et al[43], 2010NonePeriodontal intrabony defectsCase seriesAutologous periodontal ligamentImplanted into bone defect sites via surgical approachPDLPs + HA/TCP (n = 3)None3, 6, 12, 32, 42, and 72 moCAL (↓); PD (↓); GR (↑)
Chen et al[29], 2016 NCT01357785Periodontal intrabony defectsRCTAutologous periodontal ligamentImplanted into bone defect sites via surgical approachPDLSCs sheets + DBBM (n = 20)DBBM (n = 21)2 wk; 3, 6, 12 moCAL (-); PD (-); GR (-)
Iwata et al[44], 2018UMIN000005027Periodontal intrabony defectsCase seriesAutologous periodontal ligamentImplanted into bone defect sites via surgical approachPDL-derived cell sheets + β-TCP (n = 10)None3, 6, 55 ± 19 moCAL (↓); PD (↓); bone height (↑)
Vandana et al[125], 2015NonePeriodontal intrabony defectsA case reportAutologous periodontal ligamentImplanted into bone defect sites via surgical approachPeriodontal ligament soft tissue + Gelatin sponge + Cementum scrapings (n = 1)None1 wk; 3, 6, 12 moCAL (↓); PD (↓); BMD (↑)
Aimetti et al[47], 2014NonePeriodontal intrabony defectsA case reportAutologous dental pulpImplanted into bone defect sites via surgical approachPulp micrografts + Collagen sponge (n = 1)None6 mo; 1 yearPPD (↓); bone fill (↑)
Aimetti et al[46], 2018NonePeriodontal intrabony defectsCase seriesAutologous dental pulpImplanted into bone defect sites via surgical approachPulp micrografts + Collagen sponge (n = 11)None1 yearCAL (↓); PD (↓); bone fill (↑)
Aimetti et al[49], 2015NonePeriodontal intrabony defectsCase seriesAutologous dental pulpImplanted into bone defect sites via surgical approachPulp micrografts + Collagen sponge (n = 4)None6, 12 moPD (↓); CAL (↓); bone fill (↑)
Hernández-Monjaraz et al[48], 2018ISRCTN12831118Periodontal intrabony defectsA case reportAllogeneic dental pulpImplanted into bone defect sites via surgical approachDPSCs + Lyophilized collagen-polyvinylpyrrolidone sponge scaffold (n = 1)None3, 6 moPD (↓); TM (↓); bone fill (↑)
Barbier et al[57], 2018EudraCT database 2014-001913-18Post-extraction socketsSplit-mouth RCTAutologous dental pulpImplanted into postextraction socketsPulp micrografts + collagen matrix (n = 30)Collagen matrix (n = 30)6 moBMD (-); interdental septum height (-)
Cubuk et al[62], 2023NCT04641533Post-extraction socketsSplit-mouth RCTAutologous dental pulpImplanted into postextraction socketsPulp micrografts + L-PRF (n = 13)L-PRF (n = 13)7 d; 6 moPPD (-); CAL (-); vertical bone loss (-); relative bone density (-)
d’Aquino et al[58], 2009NonePost-extraction socketsSplit-mouth CCTAutologous dental pulpImplanted into postextraction socketsDental pulp stem/progenitor cells + collagen sponge (n = 7)Collagen sponge (n = 7)7 d; 1, 2, 3, 12 moRate of mineralization (↑); levels of cortical bone (↑); CAL (↓); BMP-2, VEGF (↑)
Tanikawa et al[63], 2020NCT03766217Cleft lip and palateHistorical control studyAutologous deciduous pulpPlaced into the alveolar defect via surgical approachSHED + Hydroxyapatite-collagen sponge (n = 6)rhBMP-2 + Hydroxyapatite-collagen sponge (Group I n = 8); Iliac crest bone graft (Group II n = 8)6, 12 moBone filling percentage (↑, compared with Group I at the 6-mo follow-up)
Manimaran et al[59], 2014NoneMandibular osteoradionecrosisA case reportAllogeneic dental pulpInserted into the defect after surgical curettageDPSCs + PRP + TCP (n = 1)None2, 6 moBone formation (↑)
Manimaran et al[60], 2016NoneBone defect left by the resection of mandibular ameloblastomaA case reportAutologous dental pulpPacked inside the mesh and placed over the mandible after tumor resectionDPSCs + β-TCP + PRF + SVF (n = 1)None1, 10 mo; 1.5 yearsBone regeneration (↑); no recurrence of tumor
Brunelli et al[61], 2013NoneSinus liftingA case reportAutologous dental pulpImplanted into sinus cavityPulp micrografts + Collagen sponge (n = 1)None4 moBMD (↑)
Koga et al[64], 2022NoneErectile dysfunctionCase seriesAllogeneic deciduous pulpInjected into the penisSHED-CM (n = 38)NoneAfter every injectionIIEF-5 score (↑)
Silva et al[65], 2022NCT02728115Huntington’s disease with preexisting pulmonary noduleA case reportAllogeneic deciduous pulpIntravenous administrationsSHED (n = 1)None15, 30 d; 7, 24, 32 moUnified Huntington’s disease rating scale (↓); not show long-term tropism or homing for the lung adenocarcinoma
Wang et al[93], 2010NonePlaque psoriasisA case reportAllogeneic gingivalBolus injectionGMSCs (n = 1)None3 yearsPsoriatic lesions fully cleared; no recurrence
Suda et al[67], 2022NCT04608838; JapicCTI194570Acute ischemic strokeStudy protocolAllogeneic dental pulpIntravenous administrationDPSCsPlaceboPer 15 min (1-4 h); per 30 min (4-6 h); 12, 24 h; 2, 3, 8, 31, 91, 181, 366 dNo results
Nagpal et al[68], 2016NoneChronic disability after strokeStudy protocolAutologous dental pulpImplanted into peri-infarct region via neurosurgical procedureDPSCsNone1, 6, 9, 12 moNo results
Ye et al[69], 2020ChiCTR2000031319: NCT04336254COVID-19Study protocolAllogeneic dental pulpIntravenous administrationDPSCsSaline2 h ± 30 min; 24 h ± 30 min; 90 d ± 3 dNo results
Table 3 Dental stem cell-based clinical trials registered at clinicaltrials.gov
Ref.Registration ID
Status
Diseases
Study design
Cell source
Administration route
Number of patients
Interventions
Follow-upperiod
Phase
Outcomes
Test group
Control group
-NCT04983225RecruitingPeriodontitisRandomized; parallel assignment; double-blind (participant, investigator)Dental pulpInjecting into the periodontal defect site36DPSCs (1 × 106)/site; DPSCs (5 × 106)/site; DPSCs (3-4 × 107)/three or four sites; DPSCs (1 × 107)/site; DPSCs (2 × 107)/two sitesSaline solution90, 180, 360, 720 dPhase 1
-NCT02523651UnknownPeriodontitisRandomized; parallel assignment; triple-blind (participant, investigator, outcomes Assessor)Allogeneic dental pulpInjecting into the periodontal defect site40DPSCs (1 × 106)Saline solution1 yearPhase 1/2
-NCT03386877CompletedPeriodontitisRandomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)Autologous dental pulpDelivering into intrabony defect via minimally invasive surgical technique29Micrografts of DPSCs + Collagen spongeCollagen sponge6, 12 moNot applicable
-NCT01082822UnknownPeriodontitisNonrandomized; parallel assignment; open labelPeriodontal ligamentImplanted into bone defect sites via surgical approach80PDLSCs sheet fragment + DBBM (Bio-oss); PDLSCs sheet pellets + DBBM (Bio-oss); DBBM (Bio-oss)Sham comparator4, 12, 24 wk; 1 yearPhase 1/2
-NCT03638154CompletedPeriodontitisRandomized; parallel assignment; double-blind (care provider, outcomes assessor)GingivalImplanted into bone defect sites via surgical approach20GFs + GMSCs + β-TCPβ-TCP1, 3, 7, 14 d; 6 moNot applicable
-NCT03137979UnknownPeriodontitisRandomized; parallel assignmentGingivalImplanted into bone defect sites via surgical approach30GMSCs + Collagen scaffolds; collagen scaffoldsOpen flap debridement1, 3, 6 moPhase1/2
Chen et al[29], 2016NCT01357785UnknownPeriodontitisRandomized; parallel assignment; open labelAutologous periodontal ligament35None3-12 moPhase1
Cubuk et al[62], 2023NCT04641533CompletedPost-extraction socketsSplit-mouth; randomized; crossover assignment; double-blind (investigator, outcomes assessor)Dental pulpPlacing into the extraction socket13DPSCs + L-PRFL-PRF7 d; 6 moNot applicable
-NCT02731586UnknownEdentulous alveolar ridgeSingle group assignment; open labelAllogeneic dental pulpIntroducing dental pulp-derived mesenchymal stem cells during placement of dental implants10Dental pulp-derived MSCsNone3 moEarly Phase 1
Tanikawa et al[63], 2020; Pinheiro et al[70], 2019NCT03766217CompletedCleft lip and palateRandomized; parallel assignment; single-blind (outcomes assessor)Autologous deciduous pulpPlaced into the alveolar defect via surgical approach62SHED + Hydroxyapatite-collagen spongeIliac crest autogenous bone graft15 d; 3, 6, 12 moPhase3
Tanikawa et al[63], 2020NCT01932164Completed; Has resultsCleft lip and palateSingle group assignment; open labelAutologous deciduous pulpMaxillary alveolar graft by tissue engineering5SHED + Hydroxyapatite-collagen spongeNone3, 6 moNot applicablePercentage of bone filling at 6 mo postoperatively: 89.5%
-NCT04130100UnknownKnee osteoarthritisRandomized; parallel assignment; open labelDental pulpIntraarticular injection60Low dose of DPSCs; high dose of DPSCsSodium hyaluronate12 moEarly phase 1
-NCT01814436UnknownDental pulp necrosisSingle group assignment;open labelAutologous deciduous pulp80Scaffold-free SHED-derived pelletNone3-12 moNot applicable
-NCT03957655UnknownLiver cirrhosisRandomized; parallel assignment; single-blind (outcomes assessor)Autologous deciduous pulpPeripheral vein infusion40SHED (1 × 106 cells/kg body weight)Standard medication for viral hepatitis and cirrhosis4, 8, 12, 16, 24 wkEarly phase 1
-NCT03912480UnknownType 1 diabetesSingle group assignment; open labelDeciduous pulpIntravenous drip24SHED (0.11 IU/kg body weight) + Insulin + oral hypoglycemic drugsNone1, 2, 6 wk; 2, 3, 6, 9, 12 moEarly phase 1
Suda et al[67], 2022NCT04608838CompletedAcute ischemic strokeRandomized;Parallel assignment;Quadruple-blind (Participant, Care Provider, Investigator, Outcomes Assessor);Allogeneic dental pulpIntravenously infusion79DPSCs (JTR-161, 1 × 108 cells); DPSCs (JTR-161, 3 × 108 cells)Placebo91, 366 dPhase 1/2
-NCT02728115Active, not recruitingNonrandomized; parallel assignment; open labelAllogeneic deciduous pulpIntravenous administration6SHED (Cellavita HD, 1 × 106 cells); SHED (Cellavita HD, 2 × 106 cells)None1, 4 yearsPhase 1
-NCT04219241Active, not recruitingHuntington’s diseaseSingle group assignment; open labelAllogeneic deciduous pulpIntravenous administration35SHED (Cellavita HD, 2 × 106 cells)None1, 2 yearsPhase 2/3
Wenceslau et al[71], 2022NCT03252535CompletedHuntington’s diseaseRandomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)Allogeneic deciduous pulpIntravenous administration35SHED (Cellavita HD, 1 × 106 cells); SHED (Cellavita HD, 2 × 106 cells)Physiological solution without cellsMonthly for 14 moPhase 2
Ye et al[69], 2020NCT04336254RecruitingCOVID-19Randomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)Allogeneic dental pulpIntravenous injection20DPSCs (3 × 107 cells)Saline28 dPhase 1/2
-NCT04302519UnknownCOVID-19Single group assignment; open labelDental pulpIntravenous injection24DPSCs (1 × 107 cells/kg body weight)None3, 7, 14, 28, 360 dEarly phase 1
Table 4 Dental stem cell-based clinical trials registered on the International Clinical Trials Registry Platform
Ref.Registration ID
Status
Diseases
Study design
Cell source
Administration route
Number of patients
Interventions
Follow-up period
Phase
Outcomes
Test group
Control group
-JPRN-UMIN000042791Complete: Follow-up completePeriodontitisRandomized; parallel assignment; single-blind (participants)Deciduous pulpGargle30Mouthwash containing SHED culture supernatantMouthwash without SHED culture supernatant1 moNot applicable
-ChiCTR2100051466RecruitingPeriodontitisRandomized; parallel assignment; open labelDental pulpBilateral multipoint injection on a single tooth96DPSCs (1 × 107 cells) for once; DPSCs (1 × 107 cells) for twiceSaline90, 180, 360 dPhage 0
-ChiCTR2100049178PendingPeriodontitisRandomized; parallel assignment; double-blindDental pulpLocal injection36DPSCs (1 × 106 cells) for single injection; DPSCs (5 × 106 cells) for single injection; DPSCs (1 × 107 cells) for single injection; DPSCs (1 × 107 cells) for single injection in 2 locations; DPSCs (1 × 107 cells) for single injection in 3-4 locationsNonePhage 1
Sánchez et al[42], 2020ISRCTN13093912CompletedPeriodontitisRandomized; parallel assignment; single-blind (patients and examiners)Dental pulpImplanted into bone defect sites via surgical approach20DPSCs (1 × 107 cells) + hydroxyapatite-collagen scaffoldHydroxyapatite-collagen scaffold1, 2, 4, 12, 24, 36 wk; 12, 24, 36, 48, 60 moNot applicable
-JPRN-UMIN000045926Complete: Follow-up completeWrinklesRandomized; parallel assignment; single-blind (outcomes assessor)Dental pulp12All-in-one gel containing immortalized DPSCs-CM solution and various beauty ingredientsNo treatment4 wkNot applicable
-JPRN-UMIN000043528Complete: Follow-up completeWrinklesRandomized; parallel assignment; single-blind (outcomes assessor)Dental pulp12All-in-one gel containing immortalized DPSC-CM solution and the latest peptide raw materialsNo treatment4 wkNot applicable
-JPRN-UMIN000045897Complete: Follow-up continuingHair lossNonrandomized; parallel assignment; open labelDeciduous pulpInjection22SHED-CM; after SHED-CM injection, one dose of micrografts (Rigenera) followed by another SHED-CM injection; SHED-CM injection after one dose of micrografts (Rigenera)None6 moNot applicable