Neural crest-derived mesenchymal stem cells: Fates and perspectives

Table 1 Dental stem cell-based clinical trials registered at ClinicalTrials.gov

Registration ID	Status	Diseases	Study design	Cell source	Administration route	Number of patients	Interventions		Follow-up period	Phase	Outcomes	Ref.
							Test group	Control group
NCT06097780	Not yet recruiting	Huntington’s disease	Randomized; parallel assignment; single-blind (outcomes assessor)	Dental pulp	Intravenous administrations	120	Intravenous human DPSCs administrations	Intravenous placebo administrations	1 year	Phase 3
NCT05924373	Recruiting	Periodontitis	Randomized; parallel assignment; double (participant investigator)	Dental pulp	Local injection at periodontal defect site	204	Single-dose group (DPSCs, 1.0 × 107); two-dose group (low-dose, DPSCs, 1.0 × 106); two-dose group (high-dose, DPSCs, 1.0 × 107)	Normal saline	90, 180, 360, 720 days	Phase 2
NCT05728346	Not yet recruiting	Pulp necroses	Nonrandomized; single group assignment; open label	Allogeneic deciduous pulp	Transplantation after the preparation and disinfection of the root canal of the affected teeth	30	SHED mixed with hyaluronic acid polymers	None	1, 3, 6, 12, 18, 24 months	Not applicable
NCT06043453	Recruiting	Apical periodontitis; trauma	Observational; multicenter blinded	Remaining dental pulp and apical papilla	Attraction or transplantation after root canal disinfection		With apical periodontitis	Without apical periodontitis	1, 2, 3 years	Not applicable
NCT04983225	Recruiting to active, not recruiting	Periodontitis	Randomized; parallel assignment; double-blind (participant, investigator)	Dental pulp	Injecting into the periodontal defect site	36	DPSCs (1 × 106)/site; DPSCs (5 × 106)/site; DPSCs [(3-4) × 107]/three or four sites; DPSCs (1 × 107)/site; DPSCs (2 × 107)/two sites	Saline solution	90, 180, 360, 720 days	Phase 1
NCT02523651	Unknown	Periodontitis	Randomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)	Allogeneic dental pulp	Injecting into the periodontal defect site	40	DPSCs (1 × 106)	Saline solution	1 year	Phase 1/2
NCT03386877	Completed	Periodontitis	Randomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)	Autologous dental pulp	Delivering into intrabony defect via minimally invasive surgical technique	29	Micrografts of DPSCs + collagen sponge	Collagen sponge	6, 12 months	Not applicable
NCT01082822	Unknown	Periodontitis	Nonrandomized; parallel assignment; open label	Periodontal ligament	Implanted into bone defect sites via surgical approach	80	PDLSCs sheet fragment + DBBM (Bio-oss); PDLSCs sheet pellets + DBBM (Bio-oss); DBBM (Bio-oss)	Sham comparator	4, 12, 24 weeks; 1 year	Phase 1/2
NCT03638154	Completed	Periodontitis	Randomized; parallel assignment; double-blind (care provider, outcomes assessor)	Gingival	Implanted into bone defect sites via surgical approach	20	GFs + GMSCs + β-TCP	β-TCP	1, 3, 7, 14 days; 6 months	Not applicable
NCT03137979	Unknown	Periodontitis	Randomized; parallel assignment	Gingival	Implanted into bone defect sites via surgical approach	30	GMSCs + collagen scaffolds; collagen scaffolds	Open flap debridement	1, 3, 6 months	Phase1/2
NCT01357785	Unknown	Periodontitis	Randomized; parallel assignment; open label	Autologous periodontal ligament		35		None	3-12 months	Phase1		Chen et al[174]
NCT04641533	Completed	Post-extraction sockets	Split-mouth; randomized; crossover assignment; double-blind (investigator, outcomes assessor)	Dental pulp	Placing into the extraction socket	13	DPSCs + L-PRF	L-PRF	7 days; 6 months	Not applicable		Cubuk et al[175]
NCT02731586	Unknown	Edentulous alveolar ridge	Single group assignment; open label	Allogeneic dental pulp	Introducing dental pulp-derived mesenchymal stem cells during placement of dental implants	10	Dental pulp-derived MSCs	None	3 months	Early phase 1
NCT03766217	Completed	Cleft lip and palate	Randomized; parallel assignment; single-blind (outcomes assessor)	Autologous deciduous pulp	Placed into the alveolar defect via surgical approach	62	SHED + hydroxyapatite-collagen sponge	Iliac crest autogenous bone graft	15 days; 3, 6, 12 months	Phase 3		Tanikawa et al[176], Pinheiro et al[177]
NCT01932164	Completed; has results	Cleft lip and palate	Single group assignment; open label	Autologous deciduous pulp	Maxillary alveolar graft by tissue engineering	5	SHED + hydroxyapatite-collagen sponge	None	3, 6 months	Not applicable	Percentage of bone filling at 6 months postoperatively: 89.5%	Tanikawa et al[176]
NCT04130100	Unknown	Knee osteoarthritis	Randomized; parallel assignment; open label	Dental pulp	Intraarticular injection	60	Low dose of DPSCs; high dose of DPSCs	Sodium hyaluronate	12 months	Early phase 1
NCT01814436	Unknown	Dental pulp necrosis	Single group assignment; open label	Autologous deciduous pulp		80	Scaffold-free SHED-derived pellet	None	3-12 months	Not applicable
NCT03957655	Unknown	Liver cirrhosis	Randomized; parallel assignment; single-blind (outcomes assessor)	Autologous deciduous pulp	Peripheral vein infusion	40	SHED (1 × 106 cells/kg body weight)	Standard medication for viral hepatitis and cirrhosis	4, 8, 12, 16, 24 weeks	Early phase 1
NCT03912480	Unknown	Type 1 diabetes	Single group assignment; open label	Deciduous pulp	Intravenous drip	24	SHED (0.11I U/kg body weight) + insulin + oral hypoglycemic drugs	None	1, 2, 6 weeks; 2, 3, 6, 9, 12 months	Early phase 1
NCT04608838	Completed	Acute ischemic stroke	Randomized; parallel assignment; quadruple-blind (participant, care provider, investigator, outcomes assessor)	Allogeneic dental pulp	Intravenously infusion	79	DPSCs (JTR-161, 1 × 108 cells); DPSCs (JTR-161, 3 × 108 cells)	Placebo	91, 366 days	Phase 1/2		Suda et al[178]
NCT02728115	Active, not recruiting to unknown		Nonrandomized; parallel assignment; open label	Allogeneic deciduous pulp	Intravenous administration	6	SHED (Cellavita HD, 1 × 106 cells); SHED (Cellavita HD, 2 × 106 cells)	None	1, 4 years	Phase 1
NCT04219241	Active, not recruiting to unknown	Huntington’s disease	Single group assignment; open label	Allogeneic deciduous pulp	Intravenous administration	35	SHED (Cellavita HD, 2 × 106 cells)	None	1, 2 years	Phase 2/3
NCT03252535	Completed	Huntington’s disease	Randomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)	Allogeneic deciduous pulp	Intravenous administration	35	SHED (Cellavita HD, 1 × 106 cells); SHED (Cellavita HD, 2 × 106 cells)	Physiological solution without cells	Monthly for 14 months	Phase 2		Wenceslau et al[179]
NCT04336254	Recruiting to unknown	COVID-19	Randomized; parallel assignment; triple-blind (participant, investigator, outcomes assessor)	Allogeneic dental pulp	Intravenous injection	20	DPSCs (3 × 107 cells)	Saline	28 days	Phase 1/2		Ye et al[180]
NCT04302519	Unknown	COVID-19	Single group assignment; open label	Dental pulp	Intravenous injection	24	DPSCs (1 × 107 cells/kg body weight)	None	3, 7, 14, 28, 360 days	Early phase 1

DPSCs: Dental pulp stem cells; SHED: Stem cells from human exfoliated deciduous teeth; PDLSCs: Periodontal ligament stem cells; DBBM: Deproteinized bovine bone mineral; GFs: Gingival fibroblast; GMSCs: Gingival mesenchymal stem cells; TCP: Tricalcium phosphate; PRF: Platelet-rich fibrin; MSCs: Mesenchymal stem cells; COVID-19: Coronavirus disease 2019.

Table 2 Dental stem cell-based clinical trials registered on the International Clinical Trials Registry Platform

Registration ID	Status	Diseases	Study design	Cell Source	Administration route	Number of patients	Interventions		Follow-up period	Phase	Outcomes	Ref.
							Test group	Control group
IRCT20140911019125N12	Pending	Children with type 1 diabetes	Not randomized; no placebo; not blinded	Deciduous pulp	Intravenous injection	10	SHEDs (3 × 106/kg, twice, 3 months apart)	None	3, 6, 12 months	Not applicable
RCT20140911019125N10	Pending	Hodgkin and non-Hodgkin lymphoma	Not randomized; no placebo; not blinded	Deciduous pulp	Intravenous injection	30	SHEDs (1 × 106/kg, 4 hours before the injection of hematopoietic stem cells); SHEDs (1 × 106/kg, on day 0, + 2, + 4, + 6 after hematopoietic stem cell transplantation); no SHEDs injection	None	Daily until discharge from the hospital	Not applicable
JPRN-UMIN000049760	Complete: Follow-up complete	Wrinkles	Randomized; parallel assignment; single-blind	Dental pulp		12	All-in-one gel containing immortalized human DPSCs-CM and various useful ingredients	None	4 weeks	Not applicable
CTRI/2024/10/075535	Not yet recruiting	Necrosis of pulp	Randomized; parallel assignment; double-blind	Deciduous pulp	Transplantation	30	Scaffold of fibrin glue loaded with E-nanoHA seeded with SHED	Blood clot scaffold with MTA	1, 3, 6, 12, 18, 24 months	Phase 3
JPRN-UMIN000042791	Complete: Follow-up complete	Periodontitis	Randomized; parallel assignment; single-blind (participants)	Deciduous pulp	Gargle	30	Mouthwash containing SHED culture supernatant	Mouthwash without SHED culture supernatant	1 month	Not applicable
ChiCTR2100051466	Recruiting	Periodontitis	Randomized; parallel assignment; open label		Bilateral multipoint injection on a single tooth	96	DPSCs (1 × 107 cells) for once; DPSCs (1 × 107 cells) for twice	Saline	90, 180, 360 days	Phage 0
ChiCTR2100049178	Pending	Periodontitis	Randomized; parallel assignment; double-blind	Dental pulp	Local injection	36	DPSCs (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 Locations	None		Phage 1
ISRCTN13093912	Completed	Periodontitis	Randomized; parallel assignment; single-blind (patients and examiners)	Dental pulp	Implanted into bone defect sites via surgical approach	20	DPSCs (1 × 107 cells) + hydroxyapatite-collagen scaffold	Hydroxyapatite-collagen scaffold	1, 2, 4, 12, 24, 36 weeks; 12, 24, 36, 48, 60 months	Not applicable		Sánchez et al[181]
JPRN-UMIN000045926	Complete: Follow-up complete	Wrinkles	Randomized; parallel assignment; single-blind (outcomes assessor)	Dental pulp		12	All-in-one gel containing immortalized DPSCs-CM solution and various beauty ingredients	No treatment	4 weeks	Not applicable
JPRN-UMIN000043528	Complete: Follow-up complete	Wrinkles	Randomized; parallel assignment; single-blind (outcomes assessor)	Dental pulp		12	All-in-one gel containing immortalized DPSC-CM solution and the latest peptide raw materials	No treatment	4 weeks	Not applicable
JPRN-UMIN000045897	Complete: Follow-up continuing → Complete: Follow-up complete	Hair loss	Nonrandomized;parallel assignment; open label	Deciduous pulp	Injection	22	SHED-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)	None	6 months	Not applicable

SHED: Stem cells from human exfoliated deciduous teeth; DPSCs: Dental pulp stem cells; CM: Conditioned medium; E-nanoHA: E- nanophased hydroxyapatite; MTA: Mineral trioxide aggregate.

Table 3 Neural crest-derived mesenchymal stem cells (except for dental stem cells) 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
Redondo et al[142]	EudraCT 2010-024246-30; NCT01389661	Maxillary bone cysts	Nonrandomized	Autologous alveolar bone	Surgical implantation	BioMax scaffold + MSCs (n = 9)	Contralateral control area of spongy alveolar bone without treatment	3-4, 6-8 months	Bone density (↑)
Apatzidou et al[143]	NCT02449005	Intrabony defects and periodontitis	Randomized; single-blind	Autologous alveolar bone	Transplanted into the osseous defect	MAF + Biocomplex (containing BMSCs, n = 9)	MAF + aFPL (n = 10); MAF (n = 8)	Baseline; 6 weeks; 6, 9, 12 months	TNF-α, RANKL levels in GCF gradually decreased, MMP levels were higher than baseline (6-9 months), and RANKL/OPG ratio was lower than baseline (9-12 months)
Apatzidou et al[144]	NCT02449005	Intrabony defects and periodontitis	Randomized; single-blind	Autologous alveolar bone	Transplanted into the osseous defect	MAF + Biocomplex (containing BMSCs, n = 9)	MAF + aFPL (n = 10); MAF (n = 8)	Baseline; 6 weeks; 6, 9, 12 months	Significant clinical improvements (attachment gain and PPD) but no between-group differences

MSCs: Mesenchymal stem cells; MAF: Minimal access flap; BMSCs: Bone marrow-derived mesenchymal stem cells; aFPL: Autologous fibrin/platelet lysate; TNF: Tumor necrosis factor; RANKL: Receptor activator for nuclear factor kappa B ligand; GCF: Gingival crevicular fluid; MMP: Matrix metalloproteinase; OPG: Osteoprotegerin; PPD: Periodontal probing depth.

Table 4 Neural crest-derived mesenchymal stem cells (except for dental stem cells) based clinical trials registered at ClinicalTrials.gov

Registration ID	Status	Diseases	Study design	Cell source	Administration route	Number of patients	Interventions		Follow-up period	Phase	Outcomes	Ref.
							Test group	Control group
NCT03070275	Completed	Implant therapy	Randomized; parallel assignment; single-blind (outcomes assessor)	Alveolar bone	Gently stabilized over the implant platform head partially covering the buccal bone	20	Biocomplex (aBM-MSCs/fibrin glue/collagen fleece)	No use of adjunctive grafting materials	4 months	Phage 1/2
NCT02449005	Completed	Chronic periodontitis	Randomized; parallel assignment; quadruple-blind (participant care, provider, investigator, outcomes assessor)	Autologous alveolar bone	Transplanted into the osseous defect	60	MAF + Biocomplex (containing BMSCs, n = 9)	MAF + aFPL (n = 10); MAF (n = 8)	Baseline; 6 weeks; 6, 9, 12 months	Phage 1/2		Apatzidou et al[143], Apatzidou et al[144]
NCT01389661	Completed	Maxillary cyst bone loss of substance	Single group assignment; open label	Autologous alveolar bone	Surgical implantation	11	BioMax scaffold + MSCs	Contralateral control area of spongy alveolar bone without treatment	0, 2 weeks; 2, 6 months	Phage 1/2		Redondo et al[142]
NCT06700655	Not yet recruiting	Limbal stem cells deficiency	Randomized; parallel assignment; single-blind (outcomes assessor)	Autologous stromal opacities	Cell transplantation	60	Cornea limbal stem cell; cornea limbal stem cell combined corneal stromal stem cell	Corneal transplantation	32, 48, 108 days; 6 months; 1, 2 years	Phage 1/2

aBM-MSCs: Autologous bone marrow mesenchymal stem cells; BMSCs: Bone marrow-derived mesenchymal stem cells; MAF: Minimal access flap; aFPL: Autologous fibrin/platelet lysate; MSCs: Mesenchymal stem cells.