Natural compounds and mesenchymal stem cells: implications for inflammatory-impaired tissue regeneration.

Inflammation is a common and important pathological process occurring in any part of the body and relating to a variety of diseases. Effective tissue repair is critical for the survival of impaired organisms. Considering the side effects of the currently used anti-inflammatory medications, new therapeutic agents are urgently needed for the improvement of regenerative capacities of inflammatory-impaired tissues. Mesenchymal stromal stem/progenitor cells (MSCs) are characterized by the capabilities of self-renewal and multipotent differentiation and exhibit immunomodulatory capacity. Due to the ability to modulate inflammatory phenotypes and immune responses, MSCs have been considered as a potential alternative therapy for autoimmune and inflammatory diseases. Natural compounds (NCs) are complex small multiple-target molecules mostly derived from plants and microorganisms, exhibiting therapeutic effects in many disorders, such as osteoporosis, diabetes, cancer, and inflammatory/autoimmune diseases. Recently, increasing studies focused on the prominent effects of NCs on MSCs, including the regulation of cell survival and inflammatory response, as well as osteogenic/adipogenic differentiation capacities, which indicate the roles of NCs on MSC-based cytotherapy in several inflammatory diseases. Their therapeutic effects and fewer side effects in numerous physiological processes, compared to chemosynthetic drugs, made them to be a new therapeutic avenue combined with MSCs for impaired tissue regeneration. Here we summarize the current understanding of the influence of NCs on MSCs and related downstream signaling pathways, specifically in pathological inflammatory conditions. In addition, the emerging concepts through the combination of NCs and MSCs to expand the therapeutic perspectives are highlighted. A promising MSC source from oral/dental tissues is also discussed, with a remarkable potential for MSC-based therapy in future clinical applications.

Resveratrol May Reduce the Degree of Periodontitis by Regulating ERK Pathway in Gingival-Derived MSCs.

Gingival-derived mesenchymal stem cells (GMSCs) have strong self-renewal, multilineage differentiation, and immunomodulatory properties and are expected to be applied in anti-inflammatory and tissue regeneration. However, achieving the goal of using endogenous stem cells to treat diseases and even regenerate tissues remains a challenge. Resveratrol is a natural compound with multiple biological activities that can regulate stem cell immunomodulation when acting on them. This study found that resveratrol can reduce inflammation in human gingival tissue and upregulate the stemness of GMSCs in human gingiva. In cell experiments, it was found that resveratrol can reduce the expression of TLR4, TNFα, and NFκB and activate ERK/Wnt crosstalk, thereby alleviating inflammation, promoting the proliferation and osteogenic differentiation ability of GMSCs, and enhancing their immunomodulation. These results provide a new theoretical basis for the application of resveratrol to activate endogenous stem cells in the treatment of diseases in the future.

Loading of erythropoietin on biphasic calcium phosphate bioceramics promotes osteogenesis and angiogenesis by regulating EphB4/EphrinB2 molecules.

Improving osteogenesis and angiogenesis using different cells and drugs is critical in the field of bone tissue engineering. Recent research has found that erythropoietin (EPO) plays an important role in both osteogenesis and angiogenesis. In this study, we grafted polydopamine and EPO onto the surface of biphasic calcium phosphate. The characterization and release property of the modified bioceramics were assessed. Cell proliferation, expression of osteoblastic and endothelial markers, and EphB4/EphrinB2 molecules were investigated while employing co-cultures of two different cells [rat vein endothelial cells (VECs) and rat bone marrow mesenchymal stromal cells (BMSCs)]. The modified bioceramics were finally implanted into the SD rats' femurs and followed by investigating the bone defect repair efficacy and the expression of EphB4/EphrinB2 molecules in vivo. The results indicated that the modified bioceramics could control the release of EPO continuously. The osteogenesis and angiogenesis were improved along with the increased expression of EphB4/EphrinB2 molecules. The expression of EphB4/EphrinB2 molecules was also significantly increased in vivo and the bone defect was repaired effectively. Overall, our findings demonstrated that EPO loading on biphasic calcium phosphate bioceramics could promote both osteogenesis and angiogenesis. The results suggest that EphB4/EphrinB2 may be crucial in the process. Graphical abstract.

eIF2α-ATF4 Pathway Activated by a Change in the Calcium Environment Participates in BCP-Mediated Bone Regeneration.

Biphasic calcium phosphate (BCP) ceramic is a classic bone void filler and a common basis of new materials for bone defect repair. However, the specific mechanism of BCP in osteogenesis has not been fully elucidated. Endoplasmic reticulum stress (ERs) and the subsequent PERK-eIF2α-ATF4 pathway can be activated by various factors, including trauma and intracellular calcium changes, and therefore worth exploring as a potential mechanism in BCP-mediated bone repair. Herein, a rat lateral femoral epicondyle defect model in vivo and a simulated BCP-mediated calcium environment in vitro were constructed for the analysis of BCP-related osteogenesis and the activation of ERs and the eIF2α-ATF4 pathway. An inhibitor of eIF2α dephosphorylation (salubrinal) was also used to explore the effect of the eIF2α-ATF4 pathway on BCP-mediated bone regeneration. The results showed that the ERs and eIF2α-ATF4 pathway activation were observed during 4 weeks of bone repair, with a rapid but brief increase immediately after artificial defect surgery and a re-increase after 4 weeks with the resorption of BCP materials. Mild ERs and the activated eIF2α induced by the calcium changes mediated by BCP regulated the expression of osteogenic-related proteins and had an important role during the defect repair. In conclusion, the eIF2α-ATF4 pathway activated by a change in the calcium environment participates in BCP-mediated bone regeneration. eIF2α-ATF4 and ERs could provide new directions for further studies on new materials in bone tissue engineering.

Surgical Treatment Selection in Adult Class III Patients With Maxillary Transverse Deficiency.

The purpose of this study was to investigate the frequency of three commonly used treatments for skeletal class III malocclusion with maxillary transverse deficiency (MTD) (SCM) patients in East Asian, to find a quantitative method for precise discrepancy evaluation, and to find other potential indicators for treatment selection. A total of 239 adult SCM patients were divided into3 groups according to treatments.Dentofacial features were measured and the initial skeletal discrepancy was evaluated with computer-aided surgical simulation (CASS). Relationship between the degree of skeletal transverse discrepancy (STD) and other dentofacial features were analyzed by Spearman's rank correlation. The STD in East Asian could be quantitatively grouped as: mild (<4 mm), moderate (4-8 mm), and severe (>8 mm). Most patients (81%) could be diagnosed with mild STD, and were treated without surgical expansion. The upper first molars inclination, the required relative movement and the required maxillary movement were correlated to the degree of STD. The conventional orthodontic and orthognathic treatment without surgical expansion is the most frequent choice for East Asian SCM adults. CASS facilitated analysis is useful in an accurate MTD evaluation. Some dentofacial features were closely correlated to STD, and thus were helpful for the treatment selection.

The inverted-L ramus osteotomy versus sagittal split ramus osteotomy in maxillomandibular advancement for the treatment of obstructive sleep apnea patients: A retrospective study.

This study aimed to compare the effectiveness and feasibility of inverted-L osteotomy (ILO) and sagittal split ramus osteotomy (SSRO) on obstructive sleep apnea (OSA) treatment. According to different surgery procedures, 28 OSA patients who underwent maxillomandibular advancement (MMA) were divided into 2 groups (group A: ILO, n = 9; group B: SSRO, n = 19). Polysomnography (PSG) and Epworth sleepiness scale (ESS) on T0, T1and T2 were used to evaluate the effectiveness of OSA treatments. Patients' airway structures and facial appearances were also evaluated. From T0 to T1, the mean apnea-hypopnea index (AHI,/per hour) dropped from 69.2 ± 8.4 to11.2 ± 2.4 (P < 0.01) in group A and from 54.6 ± 14.6 to 9.4 ± 5.4 (P < 0.01) in group B; LSpO2 (lowest pulse oxygen saturation, %) increased from 66.5 ± 7.7% to 88.2 ± 4.6 (P < 0.01) and from 76.6 ± 10.7%to 89.4 ± 2.4% (P < 0.01) while the mean ESS score decreased by 51% in group A and 44% in group B. Most patients (group A: 88.9%; group B: 84.3%) were satisfied with their postoperative appearance. Mild relapse was observed in both groups on T2. This study concluded that MMA containing ILO and MMA containing SSRO are both feasible and effective for selected OSA patients.

YAP regulates periodontal ligament cell differentiation into myofibroblast interacted with RhoA/ROCK pathway.

During orthodontic tooth movement (OTM), periodontal ligament cells (PDLCs) receive the mechanical stimuli and transform it into myofibroblasts (Mfbs). Indeed, previous studies have demonstrated that mechanical stimuli can promote the expression of Mfb marker α-smooth muscle actin (α-SMA) in PDLCs. Transforming growth factor ß1 (TGF-ß1), as the target gene of yes-associated protein (YAP), has been proven to be involved in this process. Here, we sought to assess the role of YAP in Mfbs differentiation from PDLCs. The time-course expression of YAP and α-SMA was manifested in OTM model in vivo as well as under tensional stimuli in vitro. Inhibition of RhoA/Rho-associated kinase (ROCK) pathway using Y27632 significantly reduced tension-induced Mfb differentiation and YAP expression. Moreover, overexpression of YAP with lentiviral transfection in PDLCs rescued the repression effect of Mfb differentiation induced by Y27632. These data together suggest a crucial role of YAP in regulating tension-induced Mfb differentiation from PDLC interacted with RhoA/ROCK pathway.

Virtual Surgical Planning Assisted Management for Three-Dimensional Dentomaxillofacial Deformities.

OBJECTIVE: Treatment of 3-dimensional dentomaxillofacial deformities remains a significant clinical challenge. This retrospective study aims to present the modalities of management for complex 3-dimensional dentomaxillofacial deformities with the assistance of virtual surgical planning (VSP) and 3-dimensional printed navigation templates. STUDY DESIGN: Ten patients diagnosed with complex 3-dimensional dentomaxillofacial deformities received treatment of combined orthodontics and orthognathic surgery. Various surgical techniques as well as bone graft and distraction osteogenesis were used under the guidance of VSP and 3-dimensional printed navigation templates according to the characteristics of each patient. Follow-up included clinical examination and studies of spiral computed tomography preoperatively and for an average of 12 months postoperatively. RESULT: The clinical outcomes of patients showed that VSP was successfully transferred to actual surgery in all the 10 patients. Three-dimensional dentomaxillofacial deformities were corrected significantly. Satisfactory profiles and occlusion were achieved. CONCLUSION: The management of 3-dimensional dentomaxillofacial deformities required comprehensive consideration and detailed surgical planning. Virtual surgical planning serves as a reliable assistance in the management of 3-dimensional dentomaxillofacial deformities.

Wnt3α and transforming growth factor-ß induce myofibroblast differentiation from periodontal ligament cells via different pathways.

Myofibroblasts are specialized cells that play a key role in connective tissue remodeling and reconstruction. Alpha-smooth muscle actin (α-SMA), vimentin and tenascin-C are myofibroblast phenotype, while α-SMA is the phenotypic marker. The observation that human periodontal ligament cells (hPDLCs) differentiate into myofibroblasts under orthodontic force has provided a new perspective for understanding of the biological and biomechanical mechanisms involved in orthodontic tooth movement. However, the cell-specific molecular mechanisms leading to myofibroblast differentiation in the periodontal ligament (PDL) remain unclear. In this study, we found that expression of Wnt3α, transforming growth factor-ß1 (TGF-ß1), α-SMA and tenascin-C increased in both tension and compression regions of the PDL under orthodontic load compared with unloaded control, suggesting that upregulated Wnt3α and TGF-ß1 signaling might have roles in myofibroblast differentiation in response to orthodontic force. We reveal in vitro that both Wnt3α and TGF-ß1 promote myofibroblast differentiation from hPDLCs. Dickkopf-1 (DKK1) impairs Wnt3α-induced myofibroblast differentiation in a ß-catenin-dependent manner. TGF-ß1 stimulates myofibroblast differentiation via a JNK-dependent mechanism. DKK1 has no significant effect on TGF-ß1-induced myofibroblastic phenotype.

Cysteine Dioxygenase Type 1 Inhibits Osteogenesis by Regulating Wnt Signaling in Primary Mouse Bone Marrow Stromal Cells.

Mesenchymal stem cells (MSCs) are multipotent cells, which can give rise to variety of cell types, including adipocytes and osteoblasts. Previously, we have shown that cysteine dioxygenase type 1 (Cdo1) promoted adipogenesis of primary mouse bone marrow stromal cells (BMSCs) and 3T3-L1 pre-adipocytes via interaction with Pparγ. However, the role of Cdo1 in osteogenesis remains unclear. Here, we demonstrated that expression of Cdo1 was elevated during osteoblastic differentiation of BMSCs in vitro. Interestingly, knockdown of Cdo1 by siRNA led to an increased expression of osteogenic related genes, elevated alkaline phosphatase (ALP) activity, and enhanced mineralization. Overexpression of Cdo1 in BMSCs inversely suppressed the osteogenesis. Furthermore, we found that overexpression of Cdo1 impaired Wnt signaling and restricted the Wnt3a induced expression of osteogenic transcriptional factors, such as Runx2 and Dlx5. Collectively, our findings indicate Cdo1 suppresses osteogenic differentiation of BMSCs, through a potential mechanism which involves in Wnt signaling reduction concomitantly.

Effects of transverse relationships between maxillary arch, mouth, and face on smile esthetics.

OBJECTIVE: To identify the ideal ratios between the widths of the maxillary arch, mouth, and face, respectively, and to determine the range of acceptable esthetic variations based on these ideal ratios. MATERIALS AND METHODS: A photograph of a young female with a harmonious smile was selected and digitally altered to produce two sets of images. The first image showed an altered intercanine width, while the second one showed an altered oral fissure breadth. These alterations were independently rated by judges, including 23 orthodontists and 30 undergraduates. The Mann-Whitney U-test was used to compare the scores given by male and female judges and those given by professional and nonprofessional judges. RESULTS: The following ideal transverse ratios were determined: intercanine width/oral fissure breadth, 0.638; oral fissure breadth/interparopia width: the distance between left and right paropia, 0.617; and intercanine width/face width at the level of the labial commissures, 0.300. A range of -10% to +10% was proposed as the thresholds of esthetic smile evaluations. It was shown that gender of the raters had no effect on the rating of photographs, nor were there any statistically significant differences between the professional and nonprofessional judges' ratings. CONCLUSIONS: Balanced transverse relationships in the facial region are important for smile esthetics, and there is a wide range of esthetically acceptable variations in the transverse relationships between the maxillary arch, mouth, and face.