Advances and Perspectives in Dental Pulp Stem Cell Based Neuroregeneration Therapies

Abstract

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.

Dental Pulp Stem Cell-Derived Secretome and Its Regenerative Potential

“…hDPSCs secrete strong immunomodulatory and anti-inflammatory cytokines, such as IL-6, IL-8, Transforming Growth Factor Beta (TGF-β), Hepatocyte Growth Factor (HGF), and Indoleamine 2,3-dioxygenase (IDO) [ 15 , 35 ]. TGF-β, HGF, and IDO are able to suppress the activation of T cells, the proliferation of peripheral blood mononuclear cells, or even allogeneic immune responses [ 15 , 38 , 53 ]. The secretion of IL-6, IL-8, and TGF-β by hDPSCs reduced the Toll-like receptor 4 (TLR-4) during neuroinflammation [ 28 ].…”

“…A study on the immunomodulatory properties of hDPSCs observed that co-culture of hDPSCs and T cells promoted T cells to secrete vascular adhesion molecules-1, intracellular adhesion molecules-1, HGF, IL-6, IL-10, and TGF-β while reducing the secretion of pro-inflammatory cytokines, including IL-2, IL-12, IL-17A, and IL-6 receptor tumor necrosis factor α (TNF-α) [ 91 ]. Moreover, the dental MSC-CM suppressed the expression of pro-inflammatory cytokines, such as; TNF-α, IL-1β, IL-4, IL-6, IL-13, IL-17, IL-18, IFN-γ, COX-2, TLR-4, and NF-κB [ 12 , 13 , 15 , 35 , 92 ]. Studies reported that, when CD4+ T cells were cocultured with hDPSCs, the T cells demonstrated a high Treg expression achieved by blocking TGF-β1 and IL-10 signaling, resulting in a low Treg count, indicating that hDPSCs require stimulatory factors to exert their effects [ 38 ].…”

“…Another mechanism with which hDPSCs spread their immunomodulatory and anti-inflammatory signals is their secreted EVs [ 12 , 35 , 53 ]. It was found that the administration of BMMSC or hDPSC-EVs can exert a protective effect by reducing inflammatory signals and has potential application in tissue regeneration [ 15 , 93 ]. Growing evidence suggests that hDPSCs and SHEDs may modify EV content in response to the environment, which shows that EVs are not only involved in extracellular signaling, but also offer innate biocompatibility and long-distance communication [ 18 , 94 ].…”

“…Manufacturing should take place in a closed and aseptic environment. The MSCs should be obtained and manipulated following good manufacturing practice (GMP) [ 13 , 14 , 15 ]. The guidelines of the regulatory agencies, established procedures, and strict safety measures should be followed, and appropriate equipment, reagents, and supplies should be used [ 8 , 10 ].…”

“…Recently, growing evidence has indicated the importance of paracrine signaling induced by MSCs as a supportive mechanism for the regeneration of damaged tissue [ 8 , 10 , 14 , 17 ]. Experimental studies showed that the repair effect observed in MSC grafts on the injured tissue was mainly caused by the secreted factors released by the stem cells, rather than cellular engraftment, in an animal model [ 15 , 18 , 19 ]. Some studies also showed that the differentiation capability of MSCs was not the predominant mechanism in repairing tissue damage in most diseases, but tissue reparative properties have also been attributed to the bioactive factors secreted by the MSCs contributing to the paracrine activity [ 8 , 11 , 14 , 17 ].…”