Potential immunomodulatory effects of stem cells from the apical papilla on Treg conversion in tissue regeneration for regenerative endodontic treatment

Abstract

Aim To evaluate the expression of Foxp3‐positive lymphocytes around newly formed tissue after regenerative endodontic treatment (RET) in vivo and investigate the effects of stem cells from the apical papilla (SCAP) on the conversion of CD4+CD25− T cells to CD4+CD25+Foxp3+ regulatory T cells (Tregs) in vitro. Methodology Three 6‐month‐old beagles with nine doubled‐rooted premolars in each dog were randomly assigned to the RET group and the control group. RET was performed after apical periodontitis had been induced in the experimental immature teeth. Three months later, the expression of Foxp3 was detected in the histological sections by immunofluorescent staining. Human SCAP and CD4+CD25− T cells from mice spleens (1 : 1 and 1 : 5) were co‐cultured in cell–cell contact or in Transwells, respectively, for 24 and 72 h in vitro. The percentage of Tregs was evaluated by flow cytometry. The results were analysed using the Fisher's exact test and analysis of variance. P < 0.05 was regarded as statistically significant. Results Inflammatory cells were present with tissue regeneration in the RET group, and Foxp3‐positive T cells were enriched around the newly formed tissues. SCAP promoted Treg conversion after 72 h in vitro. Cell–cell contact played an important role after the 24 h co‐culture, whilst soluble factors were also involved after 72 h (P < 0.05). Conclusions SCAP promoted the conversion of pro‐inflammatory T cells to Tregs in vitro. Tregs were enriched around the regenerating tissues in the root canals after RET, which may create a suitable immune microenvironment for the differentiation of SCAP. This study provides an underlying mechanism for tissue regeneration during RET.

Treg: A Promising Immunotherapeutic Target in Oral Diseases

“…Thus, the balance between the host pro-inflammatory and anti-inflammatory responses supposedly determines the progression and outcome of apical periodontitis, which is regulated by different types of CD4 + T helper cells, including at least Th1, Th2, Th17, and Treg cells ( 57 ). As a potential protective subset of CD4 + T cells, accumulating studies have revealed that the beneficial role of Treg cells in restricting the overactivity of the periapical inflammatory response ( 58 , 59 ).…”

“…In vitro, stem cells from the apical papilla (SCAP) promoted the conversion of pro-inflammatory T cells to Treg cells. It may suggest that the anti-inflammatory and anti-apoptotic abilities of upregulated Treg cells promote successful tissue repair and regeneration via releasing more cytokines and pro-healing growth factors, which may create an appropriate immune microenvironment for tissue regeneration ( 59 ).…”

PRIASE 2021 guidelines for reporting animal studies in Endodontology: explanation and elaboration

“…From Liu et al . (2019) – ‘Fig. 2 provides the key information in the legend with scale bars on images.…”

“…From Liu et al . (2019) – ‘Pulp‐like tissues and free cellular cementum‐like tissues in the root canal and cellular cementum‐like tissues on the root wall were observed. Inflammatory cells were present in the periapical area and root canal together with newly formed tissue, and most were lymphocytes (Fig.…”

Unraveling the Role of the Apical Papilla During Dental Root Maturation

“…Since the discovery of the SCAP within the apical papilla, it became clear that multipotent SCAP are highly suitable for osteogenic, adipogenic and chondrogenic differentiation ( Huang G. T. J. et al, 2009 ). Together with their immunomodulatory capacity ( Gaudin et al, 2018 ; Liu et al, 2019 ; Fehrmann et al, 2020 ), SCAP have a high potential for implementation in tissue regeneration. This offered the research community an easily accessible mesenchymal stem cell source with low ethical considerations.…”