Human dental pulp stem cells (hDPSCs) are some of the most promising stem cell types for regenerative therapies given their ability to grow in the absence of serum and their realistic possibility to be used in autologous grafts. In this review, we describe the particular advantages of hDPSCs for neuroregenerative cell therapies. We thoroughly discuss the knowledge about their embryonic origin and characteristics of their postnatal niche, as well as the current status of cell culture protocols to maximize their multilineage differentiation potential, highlighting some common issues when assessing neuronal differentiation fates of hDPSCs. We also review the recent progress on neuroprotective and immunomodulatory capacity of hDPSCs and their secreted extracellular vesicles, as well as their combination with scaffold materials to improve their functional integration on the injured central nervous system (CNS) and peripheral nervous system (PNS). Finally, we offer some perspectives on the current and possible future applications of hDPSCs in neuroregenerative cell therapies.

SUMMARY: Dental Pulp Stem Cells (DPSCs) have a demonstrated capacity to acquire neuronal-like phenotypes, suggesting their use in brain cell therapies. In the present work, we wanted to address the phenotypic fate of adult DPSCs cultured in Neurocult media (Stem Cell Technologies), a cell culture medium without serum routinely used for the expansion of adult neural stem cells (NSCs). Our results showed for the first time, that non-genetically modified adult DPSCs cultured with Neurocult generated neurosphere-like dentospheres expressing the NSC markers Nestin and GFAP, but also the vascular endothelial cell marker CD31. One month post-intracranial graft into athymic nude mice, human CD31+ or Nestin+ DPSC-derived cells were found tightly associated with brain blood vessels increasing their laminin staining. These results suggest that DPSCs integrated and contributed to an increased generation of neovasculature within brain tissue and that Neurocult medium constituted a fast and efficient way to obtain endothelial cells from human DPSCs.