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Periodontal disease is chronic inflammation that leads to the destruction of tooth-supporting periodontal tissues. We devised a novel method (“cell transfer technology”) to transfer cells onto a scaffold surface and reported the potential of the technique for regenerative medicine. The aim of this study is to examine the efficacy of this technique in periodontal regeneration and the fate of transplanted cells. Human periodontal ligament stem cells (PDLSCs) were transferred to decellularized amniotic membrane and transplanted into periodontal defects in rats. Regeneration of tissues was examined by microcomputed tomography and histological observation. The fate of transplanted PDLSCs was traced using PKH26 and human Alu sequence detection by PCR. Imaging showed more bone in PDLSC-transplanted defects than those in control (amnion only). Histological examination confirmed the enhanced periodontal tissue formation in PDLSC defects. New formation of cementum, periodontal ligament, and bone were prominently observed in PDLSC defects. PKH26-labeled PDLSCs were found at limited areas in regenerated periodontal tissues. Human Alu sequence detection revealed that the level of Alu sequence was not increased, but rather decreased. This study describes a novel stem cell transplantation strategy for periodontal disease using the cell transfer technology and offers new insight for cell-based periodontal regeneration.

Periodontal tissue is a distinctive tissue structure composed three-dimensionally of cementum, periodontal ligament (PDL) and alveolar bone. Severe periodontal diseases cause fundamental problems for oral function and general health, and conventional dental treatments are insufficient for healing to healthy periodontal tissue. Cell sheet technology has been used in many tissue regenerations, including periodontal tissue, to transplant appropriate stem/progenitor cells for tissue regeneration of a target site as a uniform tissue. However, it is still difficult to construct a three-dimensional structure of complex tissue composed of multiple types of cells, and the transplantation of a single cell sheet cannot sufficiently regenerate a large-scale tissue injury. Here, we fabricated a three-dimensional complex cell sheet composed of a bone-ligament structure by layering PDL cells and osteoblast-like cells on a temperature responsive culture dish. Following ectopic and orthotopic transplantation, only the complex cell sheet group was demonstrated to anatomically regenerate the bone-ligament structure along with the functional connection of PDL-like fibers to the tooth root and alveolar bone. This study represents successful three-dimensional tissue regeneration of a large-scale tissue injury using a bioengineered tissue designed to simulate the anatomical structure.

Regenerating periodontal ligament (PDL) tissue is a vital challenge in dentistry that aims to restore periodontal function and aesthetics. This study explores a tissue engineering strategy that combines polycaprolactone (PCL)/collagen/cellulose acetate electrospun scaffolds with collagen hydrogels to deliver curcumin-loaded ZIF-8 nanoparticles fand periodontal ligament stem cells (PDLSCs). Scaffolds were fabricated via electrospinningand collagen hydrogels incorporated PDLSCs and curcumin-loaded ZIF-8 nanoparticles (CURZIF-8) were developed using cross-linking. In vitro assays evaluated biocompatibility, anti-inflammatory, and antioxidative properties. In vivo efficacy was assessed in a rat PDL injury model using histological and ELISA analyses examining tissue regeneration and inflammatory cytokine modulation. In vitro studies demonstrated that the scaffolds effectively supported PDLSC viability and migration. CURZIF-8 hydrogels enhanced anti-inflammatory and antioxidative activities. In vivo study showed that the combined scaffold-hydrogel system significantly promoted PDL regeneration. Tissue levels of bFGF, HGF, and TGF-β that are crucial for tissue repair, angiogenesis, and cell proliferation were evaluated. Whereas, pro-inflammatory cytokines TNF-α and IL-6=were downregulated. Histological analysis confirmed the formation of organized PDL structures and improved bone-cementum integration that arekey indicators of successful periodontal regeneration. The developed scaffold-hydrogel system facilitates PDL regeneration by modulating inflammation and promoting pro-healing factor expression. This approach shows promise for advancing periodontal tissue engineering and warrants further investigation in clinical settings.

The selective in vitro expansion and differentiation of multipotent stem cells are critical steps in cell‐based regenerative therapies, while technical challenges have limited cell yield and thus affected the success of these potential treatments. The Rho GTPases and downstream Rho kinases are central regulators of cytoskeletal dynamics during cell cycle and determine the balance between stem cells self‐renewal, lineage commitment and apoptosis. Trans‐4‐[(1R)‐aminoethyl]‐N‐(4‐pyridinyl)cylohexanecarboxamidedihydrochloride (Y‐27632), Rho‐associated kinase (ROCK) inhibitor, involves various cellular functions that include actin cytoskeleton organization, cell adhesion, cell motility and anti‐apoptosis. Here, human periodontal ligament stem cells (PDLSCs) were isolated by limiting dilution method. Cell counting kit‐8 (CCK8), 5‐ethynyl‐2′‐deoxyuridine (EdU) labelling assay, cell apoptosis assay, cell migration assay, wound‐healing assay, alkaline phosphatase (ALP) activity assay, Alizarin Red S staining, Oil Red O staining, quantitative real‐time polymerase chain reaction (qRT‐PCR) were used to determine the effects of Y‐27632 on the proliferation, apoptosis, migration, stemness, osteogenic and adipogenic differentiation of PDLSCs. Afterwards, Western blot analysis was performed to elucidate the mechanism of cell proliferation. The results indicated that Y‐27632 significantly promoted cell proliferation, chemotaxis, wound healing, fat droplets formation and pluripotency, while inhibited ALP activity and mineral deposition. Furthermore, Y‐27632 induced PDLSCs proliferation through extracellular‐signal‐regulated kinase (ERK) signalling cascade. Therefore, control of Rho‐kinase activity may enhance the efficiency of stem cell‐based treatments for periodontal diseases and the strategy may have the potential to promote periodontal tissue regeneration by facilitating the chemotaxis of PDLSCs to the injured site, and then enhancing the proliferation of these cells and maintaining their pluripotency.

This study assessed the effects of photobiomodulation therapy (PBMT) with different laser wavelengths on the viability and differentiation of periodontal ligament mesenchymal stem cells (PDLMSCs) exposed to zoledronic acid (ZA). In this in vitro study, PDLMSCs were cultured with 5 µM ZA for 48 h and randomly assigned to 6 groups of positive and negative controls, and PBMT with 635 nm (2 and 4 J/cm 2 ) and 980 nm (2 and 4 J/cm 2 ) lasers. Cell viability was assessed by the methyl thiazolyl tetrazolium (MTT) assay after 24 and 72 h, and mineralized nodule formation was evaluated by Alizarin red staining. Mineralization was assessed by alkaline phosphatase (ALP) activity and expression analysis of osteocalcin (OCN), osteopontin (OPN), and RUNX2 by real-time polymerase chain reaction (PCR). Data were analyzed by one-way ANOVA and Tukey test (α = 0.05). ZA exposure in no-irradiation group decreased viability, ALP activity, mineralized nodule formation, and expression of osteogenic genes ( P  < 0.05). Cell viability in 980 nm (4 J/cm 2 ) group at 24 h and in 635 nm (4 J/cm 2 ) and 980 nm (2 and 4 J/cm 2 ) groups at 72 h was significantly higher than that in ZA group ( P  < 0.05). Mineralized nodule formation in both 980 nm groups was significantly higher than that in ZA group ( P  < 0.001). PBMT with 635 nm laser caused significant downregulation of OCN and OPN with 4 J/cm 2 and upregulation of OPN with 2 J/cm 2 ( P  < 0.05) energy density. PBMT with 980 nm laser (2 and 4 J/cm 2 ) caused significant upregulation of OCN, OPN, and RUNX2 ( P  < 0.05). PBMT with 980 nm laser (4 J/cm 2 ) in presence of ZA increased PDLMSC viability, ALP activity, mineralized nodule formation, and expression of osteogenic genes.

The aim of the study was to examine the biochemical and structural changes occurring in the periodontal ligament (PDL) during orthodontic-force application using micro-Raman spectroscopy ( μ -RS). Adolescent and young patients who needed orthodontic treatment with first premolar extractions were recruited. Before extractions, orthodontic forces were applied using a closed-coil spring that was positioned between the molar and premolar. Patients were randomly divided into three groups, whose extractions were performed after 2, 7, and 14 days of force application. From the extracted premolars, PDL samples were obtained, and a fixation procedure with paraformaldehyde was adopted. Raman spectra were acquired for each PDL sample in the range of 1000–3200 cm − 1 and the more relevant vibrational modes of proteins (Amide I and Amide III bands) and CH 2 and CH 3 modes were shown. Analysis indicated that the protein structure in the PDL samples after different time points of orthodontic-force application was modified. In addition, changes were observed in the CH 2 and CH 3 high wavenumber region due to local hypoxia and mechanical force transduction. The reported results indicated that μ -RS provides a valuable tool for investigating molecular interchain interactions and conformational modifications in periodontal fibers after orthodontic tooth movement, providing quantitative insight of time occurring for PDL molecular readjustment.

Fibroblast growth factor-2 (FGF-2) enhances the formation of new alveolar bone, cementum, and periodontal ligament (PDL) in periodontal defect models. However, the mechanism through which FGF-2 acts in periodontal regeneration in vivo has not been fully clarified yet. To reveal the action mechanism, the formation of regenerated tissue and gene expression at the early phase were analyzed in a beagle dog 3-wall periodontal defect model. FGF-2 (0.3%) or the vehicle (hydroxypropyl cellulose) only were topically applied to the defect in FGF-2 and control groups, respectively. Then, the amount of regenerated tissues and the number of proliferating cells at 3, 7, 14, and 28 days and the number of blood vessels at 7 days were quantitated histologically. Additionally, the expression of osteogenic genes in the regenerated tissue was evaluated by real-time PCR at 7 and 14 days. Compared with the control, cell proliferation around the existing bone and PDL, connective tissue formation on the root surface, and new bone formation in the defect at 7 days were significantly promoted by FGF-2. Additionally, the number of blood vessels at 7 days was increased by FGF-2 treatment. At 28 days, new cementum and PDL were extended by FGF-2. Moreover, FGF-2 increased the expression of bone morphogenetic protein 2 (BMP-2) and osteoblast differentiation markers (osterix, alkaline phosphatase, and osteocalcin) in the regenerated tissue. We revealed the facilitatory mechanisms of FGF-2 in periodontal regeneration in vivo. First, the proliferation of fibroblastic cells derived from bone marrow and PDL was accelerated and enhanced by FGF-2. Second, angiogenesis was enhanced by FGF-2 treatment. Finally, osteoblastic differentiation and bone formation, at least in part due to BMP-2 production, were rapidly induced by FGF-2. Therefore, these multifaceted effects of FGF-2 promote new tissue formation at the early regeneration phase, leading to enhanced formation of new bone, cementum, and PDL.

This study aimed to investigate the effects of different magnitudes and durations of static tensile strain on human periodontal ligament cells (hPDLCs), focusing on osteogenesis, mechanosensing and inflammation. Static tensile strain magnitudes of 0%, 3%, 6%, 10%, 15% and 20% were applied to hPDLCs for 1, 2 and 3 days. Cell viability was confirmed via live/dead cell staining. Reference genes were tested by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) and assessed. The expressions of TNFRSF11B, ALPL, RUNX2, BGLAP, SP7, FOS, IL6, PTGS2, TNF, IL1B, IL8, IL10 and PGE2 were analyzed by RT-qPCR and/or enzyme-linked immunosorbent assay (ELISA). ALPL and RUNX2 both peaked after 1 day, reaching their maximum at 3%, whereas BGLAP peaked after 3 days with its maximum at 10%. SP7 peaked after 1 day at 6%, 10% and 15%. FOS peaked after 3 days with its maximum at 3%, 6% and 15%. The expressions of IL6 and PTGS2 both peaked after 1 day, with their minimum at 10%. PGE2 peaked after 1 day (maximum at 20%). The ELISA of IL6 peaked after 3 days, with the minimum at 10%. In summary, the lower magnitudes promoted osteogenesis and caused less inflammation, while the higher magnitudes inhibited osteogenesis and enhanced inflammation. Among all magnitudes, 10% generally caused a lower level of inflammation with a higher level of osteogenesis.

Periodontal ligament stem cells (PDLSCs) are key cells that suppress periodontal damage during both the progression and recovery stages of periodontitis. Although substantial evidence has demonstrated that incubation under an inflammatory condition may accelerate senescence of PDLSCs, whether cellular senescence in response to inflammatory incubation contributes to cell dysfunction remain unexplored. In this study, we first observed inflammation‐caused PDLSC senescence in periodontitis based on comparisons of matched patients, and this cellular senescence was demonstrated in healthy cells that were subjected to inflammatory conditions. We subsequently designed further experiments to investigate the possible mechanism underlying inflammation‐induced PDLSC senescence with a particular focus on the role of long noncoding RNAs (lncRNAs). LncRNA microarray analysis and functional gain/loss studies revealed SLC30A4‐AS1 as a regulator of inflammation‐mediated PDLSC senescence. By full‐length transcriptome sequencing, we found that SLC30A4‐AS1 interacted with SRSF3 to affect the alternative splicing (AS) of TP53BP1 and alter the expression of TP53BP1‐204. Further functional studies showed that decreased expression of TP53BP1‐204 reversed PDLSC senescence, and SLC30A4‐AS1 overexpression‐induced PDLSC senescence was abolished by TP53BP1‐204 knockdown. Our data suggest for the first time that SLC30A4‐AS1 plays a key role in regulating PDLSC senescence in inflammatory environments by modulating the AS of TP53BP1. Briefly, SLC30A4‐AS1 is upregulated in senescent PDLSCs mediated by inflammation. SLC30A4‐AS1 binds the splicing factor SRSF3 to affect the alternative splicing of TP53BP1 and alter the expression of its transcript TP53BP1‐204. Knockdown of TP53BP1‐204 expression can improve the senescence of PDLSCs and improve the osteogenic differentiation ability of PDLSCs.

The periodontal ligament (PDL), a specialized fibrous connective tissue bridging cementum and alveolar bone, harbors periodontal ligament stem cells (PDLSCs) as its key regenerative cellular component. Within the oral cavity, PDLSCs are continually exposed to two predominant stimuli: mechanical forces and inflammatory signals. Under physiological conditions, PDLSCs experience cyclic loading forces during normal mastication. During orthodontic treatment, controlled mechanical force stimulates PDLSCs and mediates tooth movement. However, in pathological scenarios, pathological mechanical stress, whether from occlusal trauma or excessive orthodontic forces, can induce PDL damage, potentially leading to adverse outcomes such as root resorption or pathological alveolar bone loss. Additionally, bacterially-induced inflammation can trigger destructive PDL changes, including alveolar bone and soft tissue degradation. Crucially, PDLSCs serve as central regulators of both the pathogenesis and therapeutic resolution of these processes. This review comprehensively summarizes the modulatory roles of PDLSCs in alveolar bone remodeling under mechanical stimulation and inflammatory conditions. It covers the alterations in the biological properties and functions of PDLSCs, along with their interactions with other bone remodeling-related cells and the microenvironment. Moreover, this review emphasizes the mechanisms by which PDLSCs regulate alveolar bone remodeling.