Future possibilities of periodontal regeneration with allogeneic dental pulp stem cells

Dental stem cell biology began with the discovery of dental pulp stem cells (DPSCs) and has been one of the most important research areas in dentistry for a quarter of a century (1-3). A recent article published on a multicenter randomized clinical trial injecting allogeneic DPSCs for tissue regeneration in periodontitis (4). This study investigated efficacy and safety in a heterogeneous group of participants. The primary objective was to evaluate the regenerative capabilities of allogeneic DPSCs after injection into periodontal tissue, comparing the outcomes of DPSC treatment with standard periodontal therapies. Clinical parameters such as probing depth, clinical attachment level, and radiological assessment of bone regeneration were used. The results showed that patients who received DPSC injections showed significant improvements in clinical parameters compared to the control group. In patients treated with stem cells, the probing depth decreased more significantly, indicating improved periodontal health. A significant increase in the clinical attachment level was observed, indicating effective tissue regeneration. This was also supported by radiological imaging studies, which showed improved bone regeneration at the sites treated with DPSCs. Even before this study in 2018, the research group had already obtained approval for “Human Dental Pulp Mesenchymal Stem Cell Injection” (CXSL1700137) as an Investigational New Drug for periodontitis in China through numerous preclinical studies (5-8). These findings from basic and preclinical research were therefore pivotal for this current clinical study, as they suggested, for example, that allogeneic DPSCs are capable of tissue regeneration that is not in line with their original purpose—namely, the regeneration of the dental dentin/pulp complex. Basic research with dental stem cells cannot therefore be overestimated. In addition to the ability to differentiate into periodontal cell types, allogeneic DPSCs also appear to have an immunomodulatory effect (9), which may contribute to inhibiting inflammation and promoting healing in periodontal tissue. Even though more detailed studies on the effects of stem cells are lacking, the use of allogeneic cells is the innovative aspect of this study. It underscores the importance of the immunomodulatory properties of DPSCs for their viability and good tolerability in the allogeneic context. This study also supports the concept of stem cell banks for routine use in dentistry.

Since allogeneic DPSCs very likely also possess immunomodulatory properties, and extracellular molecules are likely involved in this process, therapeutic success could also be achieved with stem cell products such as extracellular vesicles (EVs) (10). A recently published study titled “Clinical Efficacy of Extracellular Vesicle Therapy in Periodontitis: Reduced Inflammation and Enhanced Regeneration” demonstrated the efficacy of EVs not derived from dental stem cells as a therapeutic strategy for treating periodontitis (11). The study aimed to evaluate the clinical efficacy of EV therapies, particularly in reducing inflammation and promoting periodontal tissue regeneration. Treatment with EVs led to a significant reduction in inflammatory markers in patient tissue. An improvement in periodontal tissue regeneration was observed, indicating the ability of EVs to support healing processes. The therapy was also considered safe and well-tolerated, with no serious side effects. Another research group recently published a study showing that non-human tissues can also be regenerated using EVs isolated from human gingival stem cells (GMSCs) (12). This study showed that the secretome enriched with EVs from human GMSCs significantly improves tongue muscle regeneration in rats. This study demonstrates that the therapeutic effects of stem cells may be primarily due to their secretome, which contains a variety of bioactive factors, including EVs. These results underline the potential of stem cell-based but cell-free therapeutic options in regenerative medicine.

However, it should not be forgotten that regenerative therapy with EVs is based on the remaining regenerative potential of endogenous stem cells. It is their contained biologically active molecules, such as miRNAs or cytokines, that indirectly contribute to regeneration through immunomodulatory effects (10). The development of new tissue after significant tissue loss or after age-related loss of the regenerative stem cell reservoir is therefore not possible. Stem cells have the potential for tissue development and could already form tissue or at least so-called “organoids” under in vitro conditions through tissue engineering. It can therefore be assumed that stem cells will be the ones that will enable a novel therapy. Therefore, the recently published study is an important step in the right direction. It also represents an advance on the study published approximately 10 years ago (13). In that study, “only” autologous stem cells of the periodontal ligament (PDL) were used, which are the cells responsible for periodontal regeneration. As in the current study, it was also demonstrated at that time that the autologous periodontal stem cells used were safe. However, the use of allogeneic DPSCs in the current study also opens up the prospect of using cells from dental stem cell banks. This would indeed be an important step toward the use of dental stem cells for cellular therapies. It would presumably make it possible to separate stem cell harvesting from patient treatment, simplifying routine cell therapy. Further work in basic and preclinical research will be necessary to advance routine stem cell therapies. Figure 1 illustrates possible relationships between research topics necessary for efficient cell therapy. The many diverse topics addressed by this research group could also serve as a model for future research (5-8). The new multicenter randomized clinical trial provides promising evidence for the use of allogeneic DPSCs in the treatment of periodontitis. It represents the culmination of decades of research by the working group. The significant improvements in clinical outcomes underscore the potential of DPSCs as a novel therapeutic approach for periodontal regeneration. However, further studies are needed to investigate the long-term effects and underlying mechanisms of action. This also requires basic research to better understand the proliferation and differentiation of dental stem cells. However, this study may be the beginning of new, innovative therapies that could transform the work of dentists and oral surgeons.

Figure 1 Stem cells are isolated in specialized laboratories (dental clinics) to [1] provide cells for basic research (dental cell biology). Dental cell biology not only investigates the improvement of cell isolation methods [1] and stem cell storage in cell banks [2], but also the evaluation of treatment options. These insights from dental cell biology are also used to [3] improve the practical options for cell therapy. The stored allogeneic stem cells can then be used in dental practices [3]. Alternatively, specialized dental clinics or dental practices can directly isolate autologous cells and use them for therapy [4].

Acknowledgments

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