Contribution of the Musculoskeletal Ultrasound in the Diagnosis of Seronegative Rheumatoid Arthritis.

OBJECTIVE: This is a study to investigate the value of musculoskeletal ultrasound for the early diagnosis of seronegative rheumatoid arthritis (SNRA); and to study the relationship between anti-cyclic citrullinated peptide antibody (anti-CCP) and the occurrence of bone erosion in rheumatoid arthritis (RA) detected by ultrasound. METHODS: A total of 101 patients with RA or osteoarthritis (OA) admitted to the First Affiliated Hospital of Anhui Medical University from July 2022 to December 2023 were selected and divided into the SNRA group, the SPRA group, and the OA group. The patients' metacarpophalangeal joints, proximal interphalangeal joints, distal interphalangeal joints, and wrist joints of both hands were ultrasonically examined separately, and the extensor tendon, flexor tendon, synovium, joint surface, joint cavity, and bone surface were observed. RESULTS: The differences in the detection of joint effusion, bone erosion, and joint space narrowing were not statistically significant between SNRA group and OA group (P > .05), the differences in the detection of synovitis and tenosynovitis were statistically significant (P < .05). The mean levels of synovial hyperplasia grade and synovial blood flow grade between SNRA group and OA group were significantly different (P < .05). The differences in synovitis, tenosynovitis, joint effusion, and joint space narrowing were not statistically significant between SNRA and SPRA groups (P > .05), and the differences in bone erosion were statistically significant (P < .05). The mean levels of synovial hyperplasia grade and synovial blood flow grade between SNRA group and SPRA group were significantly different (P < .05). Logistic regression analysis showed that anti-CCP antibody was an influential factor for bone erosion in RA patients (P < .05). The ROC curve was plotted, and the optimal cut-off value of anti-CCP antibody was 356.5 U/mL, at which time the AUC was 0.716, the sensitivity of diagnosing bone erosion was 0.714, the specificity was 0.694, and the Yoden index was 0.408. CONCLUSION: In summary, ultrasound is helpful for the early diagnosis of SNRA by evaluating the condition of joints, synovium, and tendon sheath, and when anti-CCP antibodies are positive, ultrasound is more likely to detect bone erosion. Ultrasound examination combined with anti-CCP antibody can further observe the joint lesions.

In-vitro and in-vivo comparative studies of treatment effects on enamel demineralization during orthodontic therapy: implications for clinical early-intervention strategy.

OBJECTIVES: This study aimed to investigate if CPP-ACP / infiltrating resin was superior in treating enamel demineralization during orthodontic therapy compared with fluoride varnish, in order to provide early-intervention implications for dental professionals. MATERIALS AND METHODS: In the in-vitro study, premolars were grouped into four: remineralization with fluoride varnish / CPP-ACP, sealing with infiltrating resin, and negative control. Experimental demineralization of enamel surfaces was analyzed using techniques of QLF, SEM, EDS and micro-hardness testing. An in-vivo intervention study was conducted on patients randomly assigned into three groups. At the baseline and every-3-month follow-up, QLF parameters were compared temporally and parallelly to yield potential implications for promotion in clinical practice. RESULTS: The in-vitro study performed on 48 experimental tooth surfaces demonstrated that sealing with infiltrating resin reduced enamel surface porosity and increased surface micro-hardness significantly. In the in-vivo intervention study on 163 tooth surfaces, it was suggested that for those who meet the criteria of -10 < ΔF < -6 and - 1000 < ΔQ < -20 at the baseline, all these treatment methods could achieve acceptable outcomes; with the rising of absolute values of ΔF and ΔQ, sealing with infiltrating resin showed more evident advantages. CONCLUSION: For enamel demineralization during orthodontic therapy, all the treatment methods involved in this study showed acceptable effectiveness but had respective characteristics in treatment effects. QLF parameters could be used as indicators for clinical early-intervention strategy with regards to this clinical issue. CLINICAL RELEVANCE: With QLF parameters, clinical early-intervention strategy for enamel demineralization during orthodontic therapy could be optimized.

Apolipoprotein E is an effective biomarker for orthodontic tooth movement in patients treated with transmission straight wire appliances.

INTRODUCTION: Orthodontic tooth movement (OTM) is the core component of orthodontic treatment and is increasingly popular for treating malocclusions. In this study, we aimed to investigate the role of apolipoprotein E (ApoE) in OTM. METHODS: Thirty patients treated with transmission straight wire technology were selected and longitudinally tracked at 2 different stages of orthodontic treatment (initial 2 months and 12 months of orthodontic treatment). Total saliva was collected and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Western blotting was used to detect the difference in ApoE expression in the saliva samples of the 2 groups. The expression of ApoE was further verified by immunohistochemical staining in a mouse model of tooth movement. RESULTS: The results of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry showed significant differences in the components of the salivary peptides in the 2 groups and peptides with a molecular weight of 2010.7 Da were predicted to be ApoE by database analysis. Western blotting further verified a significant difference in the expression of salivary ApoE in the 2 groups. In addition, an OTM model was successfully constructed in mice. The immunohistochemical staining results showed that ApoE expression significantly increased after force loading in the OTM model. CONCLUSIONS: This study indicated that ApoE participated in and played a role during OTM in patients treated with transmission straight wire technology. This relationship might be related to alveolar bone reconstruction and root resorption. The results provide new ideas for research on the mechanism of tooth movement using precision medicine based on saliva detection.

COP9 signalosome subunits protect Capicua from MAPK-dependent and -independent mechanisms of degradation.

The COP9 signalosome removes Nedd8 modifications from the Cullin subunits of ubiquitin ligase complexes, reducing their activity. Here, we show that mutations in the Drosophila COP9 signalosome subunit 1b (CSN1b) gene increase the activity of ubiquitin ligases that contain Cullin 1. Analysis of CSN1b mutant phenotypes revealed a requirement for the COP9 signalosome to prevent ectopic expression of Epidermal growth factor receptor (EGFR) target genes. It does so by protecting Capicua, a transcriptional repressor of EGFR target genes, from EGFR pathway-dependent ubiquitylation by a Cullin 1/SKP1-related A/Archipelago E3 ligase and subsequent proteasomal degradation. The CSN1b subunit also maintains basal Capicua levels by protecting it from a separate mechanism of degradation that is independent of EGFR signaling. As a suppressor of tumor growth and metastasis, Capicua may be an important target of the COP9 signalosome in cancer.

CD4+ T cells and TGFß1/MAPK signal pathway involved in the valvular hyperblastosis and fibrosis in patients with rheumatic heart disease.

The aim of this study was to investigate the roles of CD4+ T cells and transforming growth factor beta (TGFß1) in the pathological process of valvular hyperblastosis and fibrosis of patients with rheumatic heart disease (RHD). A total of 151 patients were enrolled, among whom, 78 patients were with RHD, and 73 were age and gender matched RHD negative patients. Blood samples and valve specimens were collected for analysis. Pathological changes and collagen fibers contents of valves were analyzed using HE and Masson staining. Percentage of peripheral blood CD4+ T cells was tested through flow cytometry. TGFß1 level in serum were identified by ELISA. CD4+ T cells infiltration and expression of TGFß1, p-p38, p-JNK, p-ERK in valves were detected by immunohistochemistry. The mRNA and protein levels of p38, JNK, ERK, TGFß1, I-collagen and α-SMA were detected by qRT-PCR and western blotting, respectively. The heart valve tissues of RHD patients showed higher degrees of fibrosis, calcification and lymphocytes infiltration, which were mainly CD4+ T cells. In addition, compared with control group, RHD patients had more total CD4+ T cells in peripheral blood and valve tissues. Expression of TGFß1, phosphorylation of JNK and p38, and synthesis of I-collagen in valve tissues of RHD patients were also significantly increased. Furthermore, we found a strong positive correlation between TGFß1 expression and phosphorylation of JNK and p38. CD4+ T cells, and fibrogenic cytokine TGFß1, which activate the intracellular MAPK signaling pathway may participate in the fibrosis of heart valve in RHD patients.

Sexual dimorphism of estrogen-sensitized synoviocytes contributes to gender difference in temporomandibular joint osteoarthritis.

OBJECTIVES: Temporomandibular joint osteoarthritis (TMJOA) is approximately twice as prevalent in women than in men. Synoviocytes are believed to play a critical role in joint inflammation. However, it is unknown whether synoviocytes from different genders possess sexual dimorphisms that contribute to female-predominant TMJOA. MATERIALS AND METHODS: Freund's complete adjuvant combined with monosodium iodoacetate was used to induce TMJOA in female and male rats. Histologic and radiographic features were used to evaluate TMJOA. The expression of CD68, MCP-1, iNOS, and IL-1ß was detected by immunohistochemistry and real-time PCR. Primary fibroblast-like synoviocytes (FLSs) isolated from the synovial membrane of female and male rats were used for in vitro experiments. RESULTS: Female rats showed aggravated TMJOA features as compared to male rats. Increased expression of iNOS and IL-1ß was detected in synovial membrane from female TMJOA rats as compared to male rats. Furthermore, greater amounts of CD68-positive macrophage infiltration and increased MCP-1 expression around the synovial membrane were detected in female TMJOA rats compared to males. Primary cultured FLSs from female rats showed higher sensitivity to TNF-α treatment and recruited increased macrophage migration than male FLSs. More important, ovariectomy (OVX) by ablation in female rats repressed the sensitivity of female FLSs to TNF-α treatment due to the loss of estrogen production. Blockage of the estrogen receptor repressed estrogen-potentiated TNF-α-induced pro-inflammatory cytokine expression in OVX-FLSs. Moreover, the injection of estrogen receptor antagonists relieved the cartilage destruction and bone deterioration of TMJOA in female rats. CONCLUSION: Estrogen-sensitized synoviocytes in female rats may contribute to gender differences in the incidence and progression of TMJOA.

Estradiol promotes M1-like macrophage activation through cadherin-11 to aggravate temporomandibular joint inflammation in rats.

Macrophages play a major role in joint inflammation. Estrogen is involved in rheumatoid arthritis and temporomandibular disorders. However, the underlying mechanism is still unclear. This study was done to verify and test how estrogen affects M1/M2-like macrophage polarization and then contributes to joint inflammation. Female rats were ovariectomized and treated with increasing doses of 17ß-estradiol for 10 d and then intra-articularly injected with CFA to induce temporomandibular joint (TMJ) inflammation. The polarization of macrophages and expression of cadherin-11 was evaluated at 24 h after the induction of TMJ inflammation and after blocking cadherin-11 or estrogen receptors. NR8383 macrophages were treated with estradiol and TNF-α, with or without blocking cadherin-11 or estrogen receptors, to evaluate the expression of the M1/M2-like macrophage-associated genes. We found that estradiol increased the infiltration of macrophages with a proinflammatory M1-like predominant profile in the synovium of inflamed TMJ. In addition, estradiol dose-dependently upregulated the expressions of the M1-associated proinflammatory factor inducible NO synthase (iNOS) but repressed the expressions of the M2-associated genes IL-10 and arginase in NR8383 macrophages. Furthermore, estradiol mainly promoted cadherin-11 expression in M1-like macrophages of inflamed TMJ. By contrast, blockage of cadherin-11 concurrently reversed estradiol-potentiated M1-like macrophage activation and TMJ inflammation, as well as reversed TNF-α-induced induction of inducible NO synthase and NO in NR8383 macrophages. The blocking of estrogen receptors reversed estradiol-potentiated M1-like macrophage activation and cadherin-11 expression. These results suggested that estradiol could promote M1-like macrophage activation through cadherin-11 to aggravate the acute inflammation of TMJs.

Evaluation of the facial profile of skeletal Class III patients undergoing camouflage orthodontic treatment: a retrospective study.

Objective: To identify objective metrics for evaluating the esthetics of facial profiles in skeletal Class III patients undergoing camouflage orthodontic treatment. Methods: Eighty Asian-Chinese patients classified as skeletal Class III were included. Thirty cephalometric measurements of pre- and posttreatment cephalograms were analyzed. Ten orthodontists assigned visual analog scale (VAS) scores to the pre- and posttreatment profiles based on standardized lateral photographs. Correlations between subjective VAS scores and objective measurements were assessed using Pearson correlation and stepwise multiple linear regression analysis. Results: Lower incisor (L1) protrusion, nasolabial angle, lower lip-E line distance, SNB angle, and L1 to AP plane were significantly correlated with VAS scores of pretreatment profiles of skeletal Class III patients. Factors such as retraction of the lower incisor, increased interincisal angle and overjet, reduction of lower lip-E line distance, as well as augmentation of the Z angle and nasolabial angle were significantly correlated with the changes in VAS scores post-camouflage orthodontic treatment. Stepwise multiple linear regression analysis revealed that pretreatment nasolabial angle, changes in the lower lip-E line distance, and pretreatment Pog-NB distance were the key factors influencing the posttreatment facial profile esthetics of skeletal Class III patients with camouflage orthodontic treatment. Conclusion: Several cephalometric measurements correlate with subjective facial esthetic evaluations of skeletal Class III patients. Changes in lower lip prominence, the pretreatment nasolabial angle, and Pog-NB distance are the main factors related to facial esthetics in skeletal Class III patients after camouflage orthodontic treatment.

Force-induced Caspase-1-dependent pyroptosis regulates orthodontic tooth movement.

Pyroptosis, an inflammatory caspase-dependent programmed cell death, plays a vital role in maintaining tissue homeostasis and activating inflammatory responses. Orthodontic tooth movement (OTM) is an aseptic force-induced inflammatory bone remodeling process mediated by the activation of periodontal ligament (PDL) progenitor cells. However, whether and how force induces PDL progenitor cell pyroptosis, thereby influencing OTM and alveolar bone remodeling remains unknown. In this study, we found that mechanical force induced the expression of pyroptosis-related markers in rat OTM and alveolar bone remodeling process. Blocking or enhancing pyroptosis level could suppress or promote OTM and alveolar bone remodeling respectively. Using Caspase-1-/- mice, we further demonstrated that the functional role of the force-induced pyroptosis in PDL progenitor cells depended on Caspase-1. Moreover, mechanical force could also induce pyroptosis in human ex-vivo force-treated PDL progenitor cells and in compressive force-loaded PDL progenitor cells in vitro, which influenced osteoclastogenesis. Mechanistically, transient receptor potential subfamily V member 4 signaling was involved in force-induced Caspase-1-dependent pyroptosis in PDL progenitor cells. Overall, this study suggested a novel mechanism contributing to the modulation of osteoclastogenesis and alveolar bone remodeling under mechanical stimuli, indicating a promising approach to accelerate OTM by targeting Caspase-1.

Immediately or delayed sinus augmentation after pseudocyst removal: A randomized trial.

PURPOSE: To compare clinical and histological outcomes of sinus augmentation performed immediately or 3 months after pseudocyst removal through a prospective randomized controlled study. MATERIALS AND METHODS: In total, 33 sinus augmentation procedures were performed in 31 patients. Augmentation was performed either immediately after pseudocyst removal (one-stage intervention) or after 3 months (two-stage intervention). Six months postoperatively, bone specimens were harvested, and histomorphometric analysis was performed as primary outcome. Data were recorded and evaluated for implant survival rates, marginal bone resorption, complication rate, and patient-centered outcomes (visual analogue scale [VAS]). RESULTS: There were no baseline differences between groups or dropouts. Twelve biopsies obtained for histomorphometric analysis showed that delayed sinus augmentation, when compared to immediated led to a 1.1% increased mineralized bone ratio (95% confidence interval [CI]: -15.9 to 13.7). Graft leakage and acute sinusitis occurred in one patient in the one-stage group, none in the two-stage group. No pseudocyst recurrence was observed until the end of 1-year follow-up. Median VAS scores for overall acceptance were significantly increase of 1.4 (95% CI: 0.3-2.56) in immediate group. The degree of post-operative discomfort was not significantly different, although an increase of VAS (0.52, 95% CI: -0.32 to 1.37) was observed in delay group. CONCLUSIONS: Both procedures of sinus augmentation immediately and 3 months after pseudocyst removal could obtain comparable histological outcomes and had low complication rates. Patients who underwent the one-stage procedure had a short treatment course and high satisfaction rates, but this procedure is technically challenging to perform. This clinical trial was not registered prior to participant recruitment and randomization. The clinical trial registration number is ChiCTR2200063121. The hyperlink is as follows: https://www.chictr.org.cn/showproj.html?proj=172755.

Facial profile evaluation and prediction of skeletal class II patients during camouflage extraction treatment: a pilot study.

BACKGROUND: The evaluation of the facial profile of skeletal Class II patients with camouflage treatment is of great importance for patients and orthodontists. The aim of this study is to explore the key factors in evaluating the facial profile esthetics and to predict the posttreatment facial profile esthetics of skeletal Class II extraction patients. METHODS: 124 skeletal Class II extraction patients were included. The pretreatment and posttreatment cephalograms were analyzed by a trained expert orthodontist. The facial profile esthetics of pretreatment and posttreatment lateral photographs were evaluated by 10 expert orthodontists using the visual analog scale (VAS). The correlation between subjective facial profile esthetics and objective cephalometric measurements was assessed. Three machine-learning methods were used to predict posttreatment facial profile esthetics. RESULTS: The distances from lower and upper lip to the E plane and U1-APo showed the stronger correlation with profile esthetics. The changes in lower lip to the E plane and U1-APo during extraction exhibited the stronger correlation with changes in VAS score (r = - 0.551 and r = - 0.469). The random forest prediction model had the lowest mean absolute error and root mean square error, demonstrating a better prediction accuracy and fitting effect. In this model, pretreatment upper lip to E plane, pretreatment Pog-NB and the change of U1-GAll were the most important variables in predicting the posttreatment score of facial profile esthetics. CONCLUSIONS: The maxillary incisor protrusion and lower lip protrusion are key objective indicators for evaluating and predicting facial profile esthetics of skeletal Class II extraction patients. An artificial intelligence prediction model could be a new method for predicting the posttreatment esthetics of facial profiles.

Prim-O-glucosylcimifugin ameliorates aging-impaired endogenous tendon regeneration by rejuvenating senescent tendon stem/progenitor cells.

Adult tendon stem/progenitor cells (TSPCs) are essential for tendon maintenance, regeneration, and repair, yet they become susceptible to senescence with age, impairing the self-healing capacity of tendons. In this study, we employ a recently developed deep-learning-based efficacy prediction system to screen potential stemness-promoting and senescence-inhibiting drugs from natural products using the transcriptional signatures of stemness. The top-ranked candidate, prim-O-glucosylcimifugin (POG), a saposhnikovia root extract, could ameliorate TPSC senescent phenotypes caused by long-term passage and natural aging in rats and humans, as well as restore the self-renewal and proliferative capacities and tenogenic potential of aged TSPCs. In vivo, the systematic administration of POG or the local delivery of POG nanoparticles functionally rescued endogenous tendon regeneration and repair in aged rats to levels similar to those of normal animals. Mechanistically, POG protects TSPCs against functional impairment during both passage-induced and natural aging by simultaneously suppressing nuclear factor-κB and decreasing mTOR signaling with the induction of autophagy. Thus, the strategy of pharmacological intervention with the deep learning-predicted compound POG could rejuvenate aged TSPCs and improve the regenerative capacity of aged tendons.

Deep Learning-Predicted Dihydroartemisinin Rescues Osteoporosis by Maintaining Mesenchymal Stem Cell Stemness through Activating Histone 3 Lys 9 Acetylation.

Maintaining the stemness of bone marrow mesenchymal stem cells (BMMSCs) is crucial for bone homeostasis and regeneration. However, in vitro expansion and bone diseases impair BMMSC stemness, limiting its functionality in bone tissue engineering. Using a deep learning-based efficacy prediction system and bone tissue sequencing, we identify a natural small-molecule compound, dihydroartemisinin (DHA), that maintains BMMSC stemness and enhances bone regeneration. During long-term in vitro expansion, DHA preserves BMMSC stemness characteristics, including its self-renewal ability and unbiased differentiation. In an osteoporosis mouse model, oral administration of DHA restores the femur trabecular structure, bone density, and BMMSC stemness in situ. Mechanistically, DHA maintains BMMSC stemness by promoting histone 3 lysine 9 acetylation via GCN5 activation both in vivo and in vitro. Furthermore, the bone-targeted delivery of DHA by mesoporous silica nanoparticles improves its therapeutic efficacy in osteoporosis. Collectively, DHA could be a promising therapeutic agent for treating osteoporosis by maintaining BMMSC stemness.

Self-promoted electroactive biomimetic mineralized scaffolds for bacteria-infected bone regeneration.

Infected bone defects are a major challenge in orthopedic treatment. Native bone tissue possesses an endogenous electroactive interface that induces stem cell differentiation and inhibits bacterial adhesion and activity. However, traditional bone substitutes have difficulty in reconstructing the electrical environment of bone. In this study, we develop a self-promoted electroactive mineralized scaffold (sp-EMS) that generates weak currents via spontaneous electrochemical reactions to activate voltage-gated Ca2+ channels, enhance adenosine triphosphate-induced actin remodeling, and ultimately achieve osteogenic differentiation of mesenchymal stem cells by activating the BMP2/Smad5 pathway. Furthermore, we show that the electroactive interface provided by the sp-EMS inhibits bacterial adhesion and activity via electrochemical products and concomitantly generated reactive oxygen species. We find that the osteogenic and antibacterial dual functions of the sp-EMS depend on its self-promoting electrical stimulation. We demonstrate that in vivo, the sp-EMS achieves complete or nearly complete in situ infected bone healing, from a rat calvarial defect model with single bacterial infection, to a rabbit open alveolar bone defect model and a beagle dog vertical bone defect model with the complex oral bacterial microenvironment. This translational study demonstrates that the electroactive bone graft presents a promising therapeutic platform for complex defect repair.

Neural regulation of alveolar bone remodeling and periodontal ligament metabolism during orthodontic tooth movement in response to therapeutic loading.

With increased understanding of orthodontic tooth movement (OTM) in recent years, neural regulation of OTM has become an emerging and expanding area of research. Numerous studies have shown that the nervous system, including the central and peripheral systems, regulates bone remodeling through various neuropeptides, receptor expression, etc. OTM is a unique periodontal tissue remodeling process induced by mechanical force, including changes in the periodontal ligament metabolism and alveolar bone remodeling. Various studies have shown that the nervous system participates in the OTM process and regulates the periodontal ligament metabolism. This review summarizes the current researches on neural regulation of bone remodeling and the biological responses within the periodontal ligamentduring OTM under therapeutic loading. We also discuss the issues that remain to be addressed in this field. The exploration of neural regulation on OTM not only assists us to understand the mechanism of OTM more thoroughly, but also provides a new insight to accelerate tooth movement in the future.

A hierarchical bilayer architecture for complex tissue regeneration.

Engineering a complete, physiologically functional, periodontal complex structure remains a great clinical challenge due to the highly hierarchical architecture of the periodontium and coordinated regulation of multiple growth factors required to induce stem cell multilineage differentiation. Using biomimetic self-assembly and microstamping techniques, we construct a hierarchical bilayer architecture consisting of intrafibrillarly mineralized collagen resembling bone and cementum, and unmineralized parallel-aligned fibrils mimicking periodontal ligament. The prepared biphasic scaffold possesses unique micro/nano structure, differential mechanical properties, and growth factor-rich microenvironment between the two phases, realizing a perfect simulation of natural periodontal hard/soft tissue interface. The interconnected porous hard compartment with a Young's modulus of 1409.00 ± 160.83 MPa could induce cross-arrangement and osteogenic differentiation of stem cells in vitro, whereas the micropatterned soft compartment with a Young's modulus of 42.62 ± 4.58 MPa containing abundant endogenous growth factors, could guide parallel arrangement and fibrogenic differentiation of stem cells in vitro. After implantation in critical-sized complete periodontal tissue defect, the biomimetic bilayer architecture potently reconstructs native periodontium with the insertion of periodontal ligament fibers into newly formed cementum and alveolar bone by recruiting host mesenchymal stem cells and activating the transforming growth factor beta 1/Smad3 signaling pathway. Taken together, integration of self-assembly and microstamping strategies could successfully fabricate a hierarchical bilayer architecture, which exhibits great potential for recruiting and regulating host stem cells to promote synergistic regeneration of hard/soft tissues.

Mesenchymal Stem Cell-Derived Exosome Therapy of Microbial Diseases: From Bench to Bed.

Microbial diseases are a global health threat, leading to tremendous casualties and economic losses. The strategy to treat microbial diseases falls into two broad categories: pathogen-directed therapy (PDT) and host-directed therapy (HDT). As the typical PDT, antibiotics or antiviral drugs directly attack bacteria or viruses through discerning specific molecules. However, drug abuse could result in antimicrobial resistance and increase infectious disease morbidity. Recently, the exosome therapy, as a HDT, has attracted extensive attentions for its potential in limiting infectious complications and targeted drug delivery. Mesenchymal stem cell-derived exosomes (MSC-Exos) are the most broadly investigated. In this review, we mainly focus on the development and recent advances of the application of MSC-Exos on microbial diseases. The review starts with the difficulties and current strategies in antimicrobial treatments, followed by a comprehensive overview of exosomes in aspect of isolation, identification, contents, and applications. Then, the underlying mechanisms of the MSC-Exo therapy in microbial diseases are discussed in depth, mainly including immunomodulation, repression of excessive inflammation, and promotion of tissue regeneration. In addition, we highlight the latest progress in the clinical translation of the MSC-Exo therapy, by summarizing related clinical trials, routes of administration, and exosome modifications. This review will provide fundamental insights and future perspectives on MSC-Exo therapy in microbial diseases from bench to bedside.

Force-Induced Autophagy in Periodontal Ligament Stem Cells Modulates M1 Macrophage Polarization via AKT Signaling.

Autophagy, a lysosomal degradation pathway, serves as a protective cellular mechanism in maintaining cell and tissue homeostasis under mechanical stimulation. As the mechanosensitive cells, periodontal ligament stem cells (PDLSCs) play an important role in the force-induced inflammatory bone remodeling and tooth movement process. However, whether and how autophagy in PDLSCs influences the inflammatory bone remodeling process under mechanical force stimuli is still unknown. In this study, we found that mechanical force stimuli increased the expression of the autophagy protein LC3, the number of M1 macrophages and osteoclasts, as well as the ratio of M1/M2 macrophages in the compression side of the periodontal ligament in vivo. These biological changes induced by mechanical force were repressed by the application of an autophagy inhibitor 3-methyladenine. Moreover, autophagy was activated in the force-loaded PDLSCs, and force-stimulated PDLSC autophagy further induced M1 macrophage polarization in vitro. The macrophage polarization could be partially blocked by the administration of autophagy inhibitor 3-methyladenine or enhanced by the administration of autophagy activator rapamycin in PDLSCs. Mechanistically, force-induced PDLSC autophagy promoted M1 macrophage polarization via the inhibition of the AKT signaling pathway. These data suggest a novel mechanism that force-stimulated PDLSC autophagy steers macrophages into the M1 phenotype via the AKT signaling pathway, which contributes to the inflammatory bone remodeling and tooth movement process.

Functional regeneration and repair of tendons using biomimetic scaffolds loaded with recombinant periostin.

Tendon injuries disrupt the balance between stability and mobility, causing compromised functions and disabilities. The regeneration of mature, functional tendons remains a clinical challenge. Here, we perform transcriptional profiling of tendon developmental processes to show that the extracellular matrix-associated protein periostin (Postn) contributes to the maintenance of tendon stem/progenitor cell (TSPC) functions and promotes tendon regeneration. We show that recombinant periostin (rPOSTN) promotes the proliferation and stemness of TSPCs, and maintains the tenogenic potentials of TSPCs in vitro. We also find that rPOSTN protects TSPCs against functional impairment during long-term passage in vitro. For in vivo tendon formation, we construct a biomimetic parallel-aligned collagen scaffold to facilitate TSPC tenogenesis. Using a rat full-cut Achilles tendon defect model, we demonstrate that scaffolds loaded with rPOSTN promote endogenous TSPC recruitment, tendon regeneration and repair with native-like hierarchically organized collagen fibers. Moreover, newly regenerated tendons show recovery of mechanical properties and locomotion functions.