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Small extracellular vesicles derived from hypoxic preconditioned dental pulp stem cells ameliorate inflammatory osteolysis by modulating macrophage polarization and osteoclastogenesis

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Bioactive Materials 2023年第4期22卷 326-342页

作者： Jun Tian Weiyang Chen Yuhua Xiong Qianer Li Siyi Kong Mengjie Li Chunfeng Pang Yu Qiu Zhezhen Xu Qimei Gong Xi Wei Hospital of stomatology Guanghua School of StomatologySun Yat-Sen UniversityGuangzhouGuangdong510055PR China Guangdong Provincial Key Laboratory of Stomatology GuangzhouGuangdong510055PR China

Extensive macrophage inflammatory responses and osteoclast formation are predominant during inflammatory or infective osteolysis.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(MSC-sEV)have been shown to exert therapeutic effects on bone defects.However,cultured MSCs are typically exposed to normoxia(21%O2)in vitro,which differs largely from the oxygen concentration in vivo under hypoxic conditions.It is largely unknown whether sEV derived from dental pulp stem cells(DPSCs)cultured under hypoxic conditions(Hypo-sEV)exert better therapeutic effects on lipopolysaccharide(LPS)-induced inflammatory osteolysis than those cultured under normoxic conditions(Nor-sEV)by simultaneously inhibiting the macrophage inflammatory response and osteoclastogenesis.In this study,we show that hypoxia significantly induces the release of sEV from DPSCs.Moreover,Hypo-sEV exhibit significantly improved efficacy in promoting M2 macrophage polarization and suppressing osteoclast formation to alleviate LPS-induced inflammatory calvarial bone loss compared with Nor-sEV.Mechanistically,hypoxia preconditioning markedly alters the miRNA profiles of DPSC-sEV.MiR-210-3p is enriched in Hypo-sEV,and can simultaneously induce M2 macrophage generation and inhibit osteoclastogenesis by targeting NF-κB1 p105,which attenuates osteolysis.Our study suggests a promising potential for hypoxia-induced DPSC-sEV to treat inflammatory or infective osteolysis and identifies a novel role of miR-210-3p in concurrently hindering osteoclastogenesis and macrophage inflammatory response by inhibiting NF-kB1 expression.

关键词： Dental pulp stem cells Small extracellular vesicles Macrophage Osteoclast Inflammatory osteolysis

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Improving hard metal implant and soft tissue integration by modulating the“inflammatory-fibrous complex”response

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Bioactive Materials 2023年第2期20卷 42-52页

作者： Peina Huang Jieyun Xu Lv Xie Guangqi Gao Shoucheng Chen Zhuohong Gong Xiaomei Lao Zhengjie Shan Jiamin Shi Zhaocai Zhou Zhuofan Chen Yang Cao Yan Wang Zetao Chen Hospital of stomatology Guanghua School of StomatologySun Yat-sen University and Guangdong Provincial Key Laboratory of StomatologyNo.56Lingyuan West RoadYuexiu DistrictGuangzhou510055China

Soft tissue integration is one major difficulty in the wide applications of metal materials in soft tissue-related areas.The inevitable inflammatory response and subsequent fibrous reaction toward the metal implant is one key response for metal implant-soft tissue integration.It is of great importance to modulate this inflammatory-fibrous response,which is mainly mediated by the multidirectional interaction between fibroblasts and macrophages.In this study,macrophages are induced to generate M1 and M2 macrophage immune microenvironments.Their cytokine profiles have been proven to have potentially multi-regulatory effects on fibroblasts.The multi-reparative effects of soft tissue cells(human gingival fibroblasts)cultured on metal material(titanium alloy disks)in M1 and M2 immune microenvironments are then dissected.Fibroblasts in the M1 immune microenvironment tend to aggravate the inflammatory response in a pro-inflammatory positive feedback loop,while M2 immune microenvironment enhances multiple functions of fibroblasts in soft tissue integration,including soft tissue regeneration,cell adhesion on materials,and contraction to immobilize soft tissue.Enlighted by the close interaction between macrophages and fibroblasts,we propose the concept of an“inflammatory-fibrous complex”to disclose possible methods of precisely and effectively modulating inflammatory and fibrous responses,thus advancing the development of metal soft tissue materials.

关键词： Inflammation Soft tissue Macrophage Fibroblast Metal material

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Long-term follow-up of a patient with venlafaxine-induced diurnal bruxism treated with an occlusal splint:A case report

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World Journal of Clinical Cases 2019年第4期7卷 516-524页

作者： Jia-Min Chen Ying Yan Department of Prosthodontics Guanghua School of StomatologyHospital of Stomatology Sun Yat-sen University Guangdong Provincial Key Laboratory of Stomatology

BACKGROUND Bruxism is a jaw-muscle activity characterized by the clenching or grinding of teeth. It can be divided into nocturnal bruxism and diurnal bruxism(DB). DB secondary to antidepressants is rare and refractory. Reports associated with antidepressant-induced DB are mostly anecdotal without long-term follow-up.The effect of drug intervention on antidepressant-induced DB is still contested.We herein report the first case of successful treatment of venlafaxine-induced DB with an occlusal splint.CASE SUMMARY This case report describes detailed 7-year follow-up of a patient with venlafaxineinduced DB treated with an occlusal splint. The patient who complained about involuntary daytime tooth grinding after taking venlafaxine for a period of 4 mo and was diagnosed with venlafaxine-induced DB. Subsequently, an occlusal splint with modified bilateral buccal-pterygoid pads was used to treat his tooth grinding and to protect the dental structures from tooth wearing. The patient reported remission of symptoms after several months of treatment. His grinding activity was gradually and stably controlled after 2 years, with an almost complete recovery from DB after 6 years.CONCLUSION The maxillary buccal-pterygoid splint can be used as a noninvasive approach to treat venlafaxine-induced DB.

关键词： Occlusal splint Venlafaxine Diurnal bruxism Tooth grinding Movement disorders Treatment Case report

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Apoptotic vesicles rejuvenate mesenchymal stem cells via Rab7-mediated autolysosome formation and alleviate bone loss in aging mice

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Nano Research 2023年第1期16卷 822-833页

作者： Fangcao Lei Zhiqing Huang Qianmin Ou Jiaqi Li Manqing Liu Lan Ma Lingping Tan Zhengmei Lin Xiaoxing Kou Hospital of stomatology Sun Yat-sen UniversitySouth China Center of Craniofacial Stem Cell ResearchGuangdong Provincial Key Laboratory of StomatologyGuangzhou 510080China key laboratory of Stem Cells and Tissue Engineering(Sun Yat-Sen University) Ministry of EducationGuangzhou 510080China Hospital of stomatology Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of StomatologyGuangzhou 510055China

Aging skeletons display decreased bone mass,increased marrow adiposity,and impaired bone marrow mesenchymal stem cells(MSCs).Apoptosis is a programmed cell death process that generates a large number of apoptotic vesicles(apoVs).Dysregulated apoptosis has been closely linked to senescence-associated diseases.However,whether apoVs mediate agingrelated bone loss is not clear.In this study,we showed that young MSC-derived apoVs effectively rejuvenated the nuclear abnormalities of aged bone marrow MSCs and restored their impaired self-renewal,osteo-/adipo-genic lineage differentiation capacities via activating autophagy.Mechanistically,apoptotic young MSCs generated and enriched a high level of Ras-related protein 7(Rab7)into apoVs.Subsequently,recipient aged MSCs reused apoV-derived Rab7 to restore autolysosomes formation,thereby contributing to autophagy flux activation and MSC rejuvenation.Moreover,systemic infusion of young MSC-derived apoVs enhanced bone mass,reduced marrow adiposity,and recused the impairment of recipient MSCs in aged mice.Our findings reveal the role of apoVs in rejuvenating aging-MSCs via restoring autolysosome formation and provide a potential approach for treating age-related bone loss.

关键词： apoptotic vesicles mesenchymal stem cells(MSCs) autolysosome formation Ras-related protein 7(Rab7) aging

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The inflammation influence on corneal surface after frontalis suspension surgery

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International Journal of Ophthalmology(English edition) 2018年第9期11卷 1489-1495页

作者： Kang Li Xin-Chun Zhang Xian-Xian Cai Ya-Dan Quan Rong Lu State key laboratory of Ophthalmology Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceZhongshan Ophthalmic CenterSun Yat-sen University Department of Prosthodontics Hospital of StomatologyGuangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologySun Yat-sen University

AIM： To study the influence of frontalis muscle flap suspension on ocular surface by analyzing the clinical features and inflammatory cytokines.METHODS： A prospective, observational case series. Thirty-one eyes of 25 patients with severe congenital blepharoptosis who underwent frontalis muscle flap suspension surgery with at least 6 mo of follow-up were included in the study. The main outcome measures were margin reflex distance 1（MRD_1）, degree of lagophthalmos, ocular surface disease index（OSDI）, fluorescein staining（Fl）, tear break-up time（BUT）, Schirmer I test, and inflammatory cytokine assay.RESULTS： The degrees of lagophthalmos significantly increased after surgery. The OSDI scores significantly increased 1wk postoperatively and then decreased 4wk after operation. The Fl scores reflected corneal epithelial defects in sixteen patients at early stage postoperatively. The BUT and Schirmer I test values remained stable and did not show change compared to those before surgery. The inflammatory cytokines in conjunctival epithelial cells（including IL-1β, IL-6, IL-8, TNF-α, and IL-17A） significantly increased 1wk after the surgery（P〈0.001）, then returned to the normal level at 24wk postoperatively. The levels of inflammatory cytokine IL-1β, IL-6, IL-8, TNF-α, and IL-17A elevated significantly and were positively correlated with OSDI and Fl scores.CONCLUSION： Frontalis muscle flap suspension surgery results in lagophthalmos in early period of post-operation and relieved after months. The elevation of inflammatory cytokines level may participate in the occurrence of corneal epithelial defects at the early postoperative stage.

关键词： congenital blepharoptosis frontalis muscle flap suspension corneal epithelial defects inflammation

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Orofacial inflammatory pain affects the expression of MT1 and NADPH-d in rat caudal spinal trigeminal nucleus and trigeminal ganglion

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Neural Regeneration Research 2013年第32期8卷 2991-3002页

作者： Fang Huang Hongwen He Wenguo Fan Yongliang Liu Hongyu Zhou Bin Cheng Guanghua School of stomatology Hospital of StomatologySun Yat-sen UniversityGuangdong Provincial Key Laboratory of Stomatology

Very little is known about the role of melatonin in the trigeminal system, including the function of melatonin receptor 1. In the present study, adult rats were injected with formaldehyde into the right vibrissae pad to establish a model of orofacial inflammatory pain. The distribution of melatonin re- ceptor 1 and nicotinamide adenine dinucleotide phosphate diaphorase in the caudal spinal trigeminal nucleus and trigeminal ganglion was determined with immunohistochemistry and histo- chemistry. The results show that there are significant differences in melatonin receptor 1 expression and nicotinamide adenine dinucleotide phosphate diaphorase expression in the trigeminal ganglia and caudal spinal nucleus during the early stage of orofacial inflammatory pain. Our findings sug- gest that when melatonin receptor 1 expression in the caudal spinal nucleus is significantly reduced, melatonin＇s regulatory effect on pain is attenuated.

关键词： neural regeneration pain melatonin nitric oxide maxillofacial pain caudal spinal trigeminalnucleus trigeminal ganglia mesencephalic trigeminal nucleus melatonin receptor 1 nicotinamideadenine dinucleotide phosphate diaphorase grants-supported paper neuroregeneration

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Osteoimmunomodulatory effects of biomaterial modification strategies on macrophage polarization and bone regeneration

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Regenerative Biomaterials 2020年第3期7卷 233-245页

作者： Yajuan Xie Cheng Hu Yi Feng Danfeng Li Tingting Ai Yulei Huang Xiaodan Chen Lijia Huang Jiali Tan Guangdong Provincial Key Laboratory of Stomatology Department of OrthodonticsGuanghua School of StomatologyHospital of StomatologySun Yat-sen UniversityGuangzhou 510055P.R.China

Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials.However,clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory.Currently,osteoimmunology,the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system,which includes diverse cells,cytokines,and signaling pathways.Properties of biomaterials like topography,wettability,surface charge,the release of cytokines,mediators,ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system.Based on the bone formation mechanisms,the designing methods of the biomaterials change from immune evasive to immune reprogramming.Here,we discuss the osteoimmunomodulatory effects of the new modification strategies—adjusting properties of bone biomaterials to induce a favorable osteoimmune environment.Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.

关键词： biomaterials modification osteoimmunomodulation macrophage polarization osteoimmune environment bone regeneration

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Comparative study of surface electromyography of masticatory muscles in patients with different types of bruxism

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World Journal of Clinical Cases 2022年第20期10卷 6876-6889页

作者： Kai-Wen Lan Liu-Lin Jiang Ying Yan Hospital of stomatology Sun Yat-sen UniversityGuangdong Provincial Key Laboratory of StomatologyGuanghua School of StomatologyGuangzhou 510080Guangdong ProvinceChina

BACKGROUND Bruxism is a rhythmic masticatory muscle activity that occurs involuntarily in a non-physiologically functional state.There is a lack of research classifying the functional status of masticatory muscles in patients with different mandibular movement types(centric clenching or eccentric grinding)of bruxism.AIM To assess the differences of the masticatory muscle activity in patients with different types of bruxism.METHODS A total of 21 subjects with centric bruxism(CB)and 21 subjects with eccentric bruxism(ECB)were screened from college students according to a questionnaire and their tooth wear features.Sixteen subjects with no bruxism were also recruited.The surface electromyography(EMG)signals of the temporalis anterior(TA)and superficial masseter muscle(MM)were measured in different mandibular positions and during the chewing task.The EMG amplitude and chewing cycle duration parameters were then analyzed.RESULTS The CB group showed fewer muscle maximal motor units,with the MM being more pronounced,a higher proportion of muscle contractions to be recruited for the same load of chewing activity,and a longer chewing cycle.The ECB group showed more TA maximal motor units and higher MM activity on the nonworking side in unilateral chewing.CONCLUSION CB mainly affects the MM,and patients with CB show reduced masticatory muscle contraction efficiency and chewing cycle efficiency.ECB mainly affects the TA,and patients with ECB show enhanced contraction of non-functional lateral muscle bundles.

关键词： Bruxism Electromyography Masticatory muscles Mastication Tooth wear Classification

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SPDEF suppresses head and neck squamous cell carcinoma progression by transcriptionally activating NR4A1

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International Journal of Oral Science 2021年第4期13卷 370-380页

作者： Yanting Wang Xianyue Ren Weiyu Li Ruoyan Cao Suyang Liu Laibo Jiang Bin Cheng Juan Xia Hospital of stomatology Sun Yat-sen UniversityGuangzhouChina Guangdong Provincial Key Laboratory of Stomatology GuangzhouChina Guanghua School of stomatology Sun Yat-sen UniversityGuangzhouChina

SAM pointed domain containing E26 transformation-specific transcription factor(SPDEF)plays dual roles in the initiation and development of human malignancies.However,the biological role of SPDEF in head and neck squamous cell carcinoma(HNSCC)remains unclear.In this study,the expression level of SPDEF and its correlation with the clinical parameters of patients with HNSCC were determined using TCGA-HNSC,GSE65858,and our own clinical cohorts.CCK8,colony formation,cell cycle analysis,and a xenograft tumor growth model were used to determine the molecular functions of SPDEF in HNSCC.ChIP-qPCR,dual luciferase reporter assay,and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in HNSCC.Compared with normal epithelial tissues,SPDEF was significantly downregulated in HNSCC tissues.Patients with HNSCC with low SPDEF mRNA levels exhibited poor clinical outcomes.Restoring SPDEF inhibited HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest,while silencing SPDEF promoted cell proliferation in vitro.The xenograft tumor growth model showed that tumors with SPDEF overexpression had slower growth rates,smaller volumes,and lower weights.SPDEF could directly bind to the promoter region of NR4A1 and promoted its transcription,inducing the suppression of AKT,MAPK,and NF-κB signaling pathways.Moreover,silencing NR4A1 blocked the suppressive effect of SPDEF in HNSCC cells.Here,we demonstrate that SPDEF acts as a tumor suppressor by transcriptionally activating NR4A1 in HNSCC.Our findings provide novel insights into the molecular mechanism of SPDEF in tumorigenesis and a novel potential therapeutic target for HNSCC.

关键词： inhibited SPD NR4A1

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The polycaprolactone/silk fibroin/carbonate hydroxyapatite electrospun scaffold promotes bone reconstruction by regulating the polarization of macrophages

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Regenerative Biomaterials 2022年第1期9卷 533-547页

作者： Xiaoshi Jia Jing Zhou Jinqiu Ning Maoquan Li Yitong Yao Xiaodong Wang Yutao Jian Ke Zhao Department of Prosthodontics Guanghua School of StomatologyHospital of StomatologySun Yat-sen UniversityGuangzhouGuangdong 510055China Guangdong Provincial Key Laboratory of Stomatology GuangzhouGuangdong 510055China

Macrophages are known to modulate the osteogenic environment of bone regeneration elicited by biological bone grafts.Alteration in certain chemical components tends to affect macrophages polarization.Comparatively to hydroxyapatite(HAp),carbonate hydroxyapatite(CHA)consists of 7.4(wt%)carbonate ions and more closely resembles the mineral content of bone.It remains unknown whether CHA scaffolds or HA scaffolds have better osteogenic properties.In this study,we fabricated PCL/SF scaffold,PCL/SF/HAp scaffold and PCL/SF/CHA scaffold using the electrospinning technique.Despite comparable mechanical properties,the PCL/SF/CHA scaffold exhibited better osteogenic properties than the PCL/SF/HAp scaffold.Although no significant differences were observed between the two scaffolds for promoting osteoblast differentiation in vitro,the PCL/SF/CHA group appeared to be more effective at promoting bone regeneration in cranial defects in vivo.The PCL/SF/CHA scaffold was found to promote macrophage polarization toward M2 via activating the JAK/STAT5 pathway which caused a pro-osteogenic microenvironment to facilitate osteoblast differentiation.The results of this study indicated a higher potential of CHA to substitute HAp in the production of bone scaffolds for better bone regeneration.

关键词： bone reconstruction PCL/SF/CHA scaffold macrophage polarization electrospinning

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