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Functional Dental Pulp Regeneration: Basic Research and Clinical Translation

Zhuo Xie, Zongshan Shen, Peimeng Zhan and 5 more

International Journal of Molecular Sciences · 2021 · Review · CC BY

doi:10.3390/ijms22168991 (opens in a new tab)

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Abstract

Pulpal and periapical diseases account for a large proportion of dental visits, the current treatments for which are root canal therapy (RCT) and pulp revascularisation. Despite the clinical signs of full recovery and histological reconstruction, true regeneration of pulp tissues is still far from being achieved. The goal of regenerative endodontics is to promote normal pulp function recovery in inflamed or necrotic teeth that would result in true regeneration of the pulpodentinal complex. Recently, rapid progress has been made related to tissue engineering-mediated pulp regeneration, which combines stem cells, biomaterials, and growth factors. Since the successful isolation and characterisation of dental pulp stem cells (DPSCs) and other applicable dental mesenchymal stem cells, basic research and preclinical exploration of stem cell-mediated functional pulp regeneration via cell transplantation and cell homing have received considerably more attention. Some of this effort has translated into clinical therapeutic applications, bringing a ground-breaking revolution and a new perspective to the endodontic field. In this article, we retrospectively examined the current treatment status and clinical goals of pulpal and periapical diseases and scrutinized biological studies of functional pulp regeneration with a focus on DPSCs, biomaterials, and growth factors. Then, we reviewed preclinical experiments based on various animal models and research strategies. Finally, we summarised the current challenges encountered in preclinical or clinical regenerative applications and suggested promising solutions to address these challenges to guide tissue engineering-mediated clinical translation in the future.

Figures4

From PubMed Central, U.S. National Library of Medicine.

Figure 1
Histological and clinical goals of pulp regeneration. Dental pulp may be damaged by dental caries, accidental trauma, or iatrogenic causes. The success of pulp regeneration should be defined by (A) histological and (B) clinical measures. Reconstruction of the pulpodentinal complex through angiogenesis and neurogenesis could yield histologically successful regeneration following cervical and apical dentin formation. Clinical success includes elimination of clinical symptoms such as pain and bone resorption, return of physiological functions, and increased root wall thickness and/or increased root length.
Full legend
Histological and clinical goals of pulp regeneration. Dental pulp may be damaged by dental caries, accidental trauma, or iatrogenic causes. The success of pulp regeneration should be defined by (A) histological and (B) clinical measures. Reconstruction of the pulpodentinal complex through angiogenesis and neurogenesis could yield histologically successful regeneration following cervical and apical dentin formation. Clinical success includes elimination of clinical symptoms such as pain and bone resorption, return of physiological functions, and increased root wall thickness and/or increased root length.
Open Figure 1 full size (opens in a new tab)

Figure 2
Full legend
Three key elements in pulp regeneration: dental stem cells, biomaterials, and growth factors.
Open Figure 2 full size (opens in a new tab)

Figure 3
Transcriptional (A), posttranscriptional (B), and epigenetic (C) regulation of KLF4 in DPSCs. KLF4 could directly upregulate the expression levels of Dmp1 and Dspp by binding to their promoters; similarly, NFIC and SP1 could regulate KLF4 expression by binding to the promoter region of Klf4. Sp1 was able to function as a ceRNA of Klf4 as well. Demethylation of the SP1/KLF4 binding motif enhanced the efficiency of SP1 binding and transcriptional regulation of KLF4. Additionally, KLF4 could recruit the histone acetylases P300 and HDAC3 to transactivate the expression of Dmp1 and Sp7. Complicated regulatory networks among the Sp1/Klf4/Dmp1, Sp1/Klf4/Dspp, and Sp1/Klf4/Sp7 axes need further investigation.
Full legend
Transcriptional (A), posttranscriptional (B), and epigenetic (C) regulation of KLF4 in DPSCs. KLF4 could directly upregulate the expression levels of Dmp1 and Dspp by binding to their promoters; similarly, NFIC and SP1 could regulate KLF4 expression by binding to the promoter region of Klf4. Sp1 was able to function as a ceRNA of Klf4 as well. Demethylation of the SP1/KLF4 binding motif enhanced the efficiency of SP1 binding and transcriptional regulation of KLF4. Additionally, KLF4 could recruit the histone acetylases P300 and HDAC3 to transactivate the expression of Dmp1 and Sp7. Complicated regulatory networks among the Sp1/Klf4/Dmp1, Sp1/Klf4/Dspp, and Sp1/Klf4/Sp7 axes need further investigation.
Open Figure 3 full size (opens in a new tab)

Figure 4
Comparison of three optimised strategies for pulp regeneration. (A) Novel culture methods for transplanted dental stem cells, such as three-dimensional spheroid culture systems, cell sheets, and cell aggregates, are beneficial for determining the optimal regenerative subpopulations and mimic pro-regenerative ECM, while some limitations of allogeneic transplantation cannot be avoided. (B) Exosomes used for pulp regeneration could be selected from alternative lineage-specific donor cells; however, high costs in isolation, identification, and administration before application may limit their large-scale production. Further investigations must focus on precise targeting and uptake testing. (C) An exogenous growth factor-mediated cell homing approach would be an operable and economical choice for pulp regeneration, although a wide variation in growth factor types, applied dosages, and delivery orders among recipients may lead to unpredictable outcomes.
Full legend
Comparison of three optimised strategies for pulp regeneration. (A) Novel culture methods for transplanted dental stem cells, such as three-dimensional spheroid culture systems, cell sheets, and cell aggregates, are beneficial for determining the optimal regenerative subpopulations and mimic pro-regenerative ECM, while some limitations of allogeneic transplantation cannot be avoided. (B) Exosomes used for pulp regeneration could be selected from alternative lineage-specific donor cells; however, high costs in isolation, identification, and administration before application may limit their large-scale production. Further investigations must focus on precise targeting and uptake testing. (C) An exogenous growth factor-mediated cell homing approach would be an operable and economical choice for pulp regeneration, although a wide variation in growth factor types, applied dosages, and delivery orders among recipients may lead to unpredictable outcomes.
Open Figure 4 full size (opens in a new tab)

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