**Background:** Since dental pulp stem cells (DPSCs) were first reported in 2000, six types of human dental stem cells (DSCs) have been isolated. DSCs originate from the craniofacial neural crest and exhibit dental-like tissue differentiation potential and neuro-ectodermal features. Dental follicle stem cells (DFSCs) are unique among DSCs as they are obtained at the early developing stage of the tooth prior to eruption. The dental follicle is an ectomesenchyme-derived loose connective tissue that plays a critical role in tooth eruption and gives rise to supporting tooth tissues including cementum, alveolar bone, and periodontal ligament. Compared to other dental tissues, dental follicle tissue has the advantage of large tissue volume, which is essential for obtaining sufficient cells for clinical applications.
**Methods:** This is a narrative review summarizing and commenting on the properties, application potential, and clinical transformation value of DFSCs. The authors synthesized findings from preclinical studies, animal models, and early clinical trials involving DFSCs and other DSCs for oral and neurological disease treatment.
**Key Results:** DFSCs exhibit several superior properties compared to other DSCs: (1) significantly higher cell proliferation rate and colony-formation capacity than DPSCs; (2) more similar protein profiles to cranial neural crest cells (CNCCs) than DPSCs, with high potency in odontogenic differentiation in vitro; (3) better inhibitory effects on proinflammatory lymphocyte proliferation and better promotion of anti-inflammatory Treg cells than SHEDs and DPSCs. For periodontal regeneration, DFSC sheets formed periodontal tissue-like structures including cementum-like structures and periodontal ligament with abundant blood vessels after transplantation into nude mice. DFSCs pre-exposed to Hertwig's epithelial root sheath cells (HERSCs) showed enhanced cementum and periodontal ligament-like tissue formation at 5 weeks after implantation into rat submentum. Lipopolysaccharide (LPS) preconditioning upregulated osteogenic and adhesion-related proteins in DFSC sheets and improved canine periodontal regeneration. For pulp regeneration, DFSC sheets combined with treated dentin matrix (TDM) produced new dentin pulp-like tissues after 8 weeks in mice, and DFSCs with native dental pulp extracellular matrix (NDPE) and TDM generated dentin-pulp complex-like tissues after 12 weeks in miniature swine jaws. For tooth root regeneration, shape-optimized TDM scaffolds with DFSCs transplanted into swine alveolar bone with ceramic crowns remained stable for 3 months and allowed masticatory function. In nonhuman primates, DFSC sheet-based biological root complexes restored occlusal function for 2 years. For spinal cord injury (SCI), DFSCs promoted functional recovery by reducing inflammatory response, promoting neurite regeneration, reducing progressive hemorrhagic necrosis, and differentiating into mature neurons and oligodendrocytes but not astrocytes. For Parkinson's disease (PD), DFSCs transplanted into PD mice survived for more than 6 weeks, increased dopaminergic neuron numbers, and differentiated into tyrosine hydroxylase-positive cells. DFSCs also demonstrated immunomodulatory capacity by suppressing proinflammatory cytokines (MCP-1, IL-1, IL-6, TNF-α) and increasing anti-inflammatory cytokines (IL-10) and M2 macrophage polarization in acute lung injury models. In rheumatoid arthritis patient PBMCs, DFSCs suppressed T lymphocyte proliferation and TNF-α secretion while increasing Tregs and IL-10. Cryopreservation preserved DFSC biological properties including proliferation ability, surface markers, and tri-lineage differentiation capacities after 3 months of storage.
**Clinical Implications:** DFSCs represent a promising cell source for regenerative medicine with natural advantages over other DSCs, including larger tissue volume, higher proliferation rates, better immunomodulation, and neural crest origin. Cryopreservation enables DFSCs to be used as off-the-shelf products. For future clinical applications, the authors recommend establishing potency assessment and screening criteria including donor screening, culture system optimization, and detection of cytokines/markers associated with immunomodulation (IL-4, IL-10), dental tissue regeneration (VEGF, dentin sialophosphoprotein), and neural regeneration (Nestin, GDNF). While SHEDs, DPSCs, PDLSCs, and GMSCs have already entered clinical use, clinical trials of DFSCs are forthcoming. The combination of DFSCs with appropriate scaffold materials and preconditioning strategies (such as LPS or HERSC preconditioning) may further enhance therapeutic potential.