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Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis

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International Journal of Oral Science 2018年第3期10卷 168-173页

作者： Xiuli Zhang Nannan Han Guoqing Li Haoqing Yang Yangyang Cao Zhipeng Fan Fengqiu Zhang Department of Periodontology Capital Medical University School of Stomatology laboratory of molecular Signaling and Stem Cells therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology

Periodontitis is an inflammatory autoimmune disease. Treatment should alleviate inflammation, regulate the immune reaction and promote periodontal tissue regeneration. Icariin is the main active ingredient of Epimedii Folium, and it is a promising compound for the enhancement of mesenchymal stem cell function, promotion of bone formation, inhibition of bone resorption, alleviation of inflammation and regulation of immunity. The study investigated the effect of icariin on periodontal tissue regeneration in a minipig model of periodontitis. The minipig model of periodontitis was established. Icariin was injected locally. The periodontal clinical assessment index, a computed tomography(CT) scan, histopathology and enzyme-linked immune sorbent assay(ELISA)were used to evaluate the effects of icariin. Quantitative analysis results 12 weeks post-injection demonstrated that probing depth,gingival recession, attachment loss and alveolar bone regeneration values were(3.72 ± 1.18) mm vs.(6.56 ± 1.47) mm,(1.67 ± 0.59)mm vs.(2.38 ± 0.61) mm,(5.56 ± 1.29) mm vs.(8.61 ± 1.72) mm, and(25.65 ± 5.13) mm3 vs.(9.48 ± 1.78) mm3 in the icariin group and0.9% NaCl group, respectively. The clinical assessment, CT scan, and histopathology results demonstrated significant enhancement of periodontal tissue regeneration in the icariin group compared to the 0.9% NaCl group. The ELISA results suggested that the concentration of interleukin-1 beta(IL-1β) in the icariin group was downregulated compared to the 0.9% NaCl group, which indicates that local injection of icariin relieved local inflammation in a minipig model of periodontitis. Local injection of icariin promoted periodontal tissue regeneration and exerted anti-inflammatory and immunomodulatory function. These results support the application of icariin for the clinical treatment of periodontitis.

关键词： Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis ELISA

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Wharton’s jelly MSC-derived extracellular vehicles-loaded hyaluronic acid-alginate adhesives for treatment of osteoarthritis

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Journal of Materials Science & Technology 2023年第11期142卷 240-252页

作者： Yanhong Zhao Xige Zhao Hainan Xu Yi Xing Tengling Wu Xun Sun Mingjie Kuang Xinlong Ma Wenguang Liu Qiang Yang School and Hospital of Stomatology Tianjin Medical UniversityTianjin 300070China School of Materials Science and Engineering Tianjin Key Laboratory of Composite and Functional MaterialsTianjin UniversityTianjin 300350China Department of Spine Surgery Tianjin HospitalTianjin UniversityTianjin 300211China laboratory of molecular Signaling and Stem Cells therapy Molecular Laboratory for Gene Therapy and Tooth RegenerationBeijing Key Laboratory of Tooth Regeneration and Function ReconstructionCapital Medical University School of StomatologyBeijing 100050China Department of Orthopedics the Provincial Hospital Affiliated to Shandong UniversityShandong 250014China

The repair of cartilage injury caused by osteoarthritis(OA)has long plagued clinicians.Mesenchymal stem cell(MSC)-derived small extracellular vesicles(sEVs)show great potential in cartilage regeneration and immunoregulation to realise cell-free therapy.However,unprotected sEVs are prone to be washed away by the flow of fluids and degraded in vivo.In this work,we successfully revealed that human Wharton’s jelly of umbilical cord-derived MSC(hWJMSC)sEVs promote proliferation,inhibit apoptosis,and attenuate the inflammation of chondrocytes in vitro.In light of the long period required for cartilage regeneration,we synthesised an injectable and adhesive aldehyded sodium alginate crosslinked acylhydrazide-modified hyaluronic acid(ALG-CHO/HHA)hydrogel loaded with sEVs to boost the reparative effect of the sEVs.The hydrogel-bearing sEVs was injected into cartilage defects where they adhered to the cartilage surface.In this configuration,the sEVs were delivered in a sustainable manner with the degradation of the hydrogel at the injury sites,thus contributing to highly efficient cartilage repair by regulating the regenerative and immune microenvironment.The ALG-CHO/HHA-sEV platform meets the clinical demand for long-lasting repair with a single injection.Thus,this work provides a new idea and theoretical basis for the clinical application of sEVs in the treatment of OA.

关键词： Extracellular vesicles Hydrogel Osteoarthritis Cartilage regeneration

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Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21

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Science China(Life Sciences) 2022年第11期65卷 2218-2232页

作者： Xiaoyu Li Liang Feng Chunmei Zhang Jinsong Wang Songlin Wang Lei Hu Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function ReconstructionBeijing Laboratory of Oral HealthCapital Medical University School of StomatologyBeijing 100050China Immunology Research Center for Oral and Systemic Health Beijing Friendship HospitalCapital Medical UniversityBeijing 100050China Department of Biochemistry and molecular Biology Capital Medical University School of Basic MedicineBeijing 100069China laboratory for Oral and general Health Integration and Translation Beijing Tiantan HospitalCapital Medical UniversityBeijing 100070China Research Unit of tooth Development and regeneration Chinese Academy of Medical SciencesBeijing 100700China Department of Prosthodontics Capital Medical University School of StomatologyBeijing 100050China

Cellular senescence affects the efficacy of mesenchymal stem cells(MSCs)-mediated tissue regeneration.Insulin-like growth factor binding proteins-7(IGFBP7),as a member of the IGF family,is associated with osteogenic differentiation and the senescence of MSCs,but its exact function and mechanism remain unclear.We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs(DPSCs),as observed in the gain-of-function and lossof-function analyses,the senescence-associated marker p21 showed the most pronounced expression changes.We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism,resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter,thereby reducing the transcription of p21,which ultimately prevents DPSCs senescence and promotes tissue regeneration.The activation of the mitochondrial electron transport chain(ETC)by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7,whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression.In conclusion,our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription,suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.

关键词： dental pulp-derived mesenchymal stem cells insulin-like growth factor binding protein 7 senescence metabolism SIRT1 p21

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Inorganic nitrate alleviates the senescence-related decline in liver function

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Science China(Life Sciences) 2018年第1期61卷 24-34页

作者： Haifeng Wang Lei Hu Le Li Xiaoshan Wu Zhipeng Fan Chunmei Zhang Jinsong Wang Jidong Jia Songlin Wang Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing 100050 China Department of Stomatology Beijing Bo'ai Hospital China Rehabilitation Research Center School of Rehabilitation Capital Medical University Beijing 100068 China laboratory of molecular Signaling and Stem Cells therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Beijing 100050 China Department of Btochemtstry and molecular Biology Capital Medical University School of Basic Medical Sciences Beijing 100069 China Liver Research Center Beijing Friendship Hospital Capital Medical University Beijing 100050 China

Senescence-related decline in liver function is a common complication in the elderly that can lead to impaired health in older individuals.Dietary nitrate supplements have physiological and therapeutic effects on organ function by nitrate(NO_3^-)-nitrite(NO_2^-)-nitric oxide(NO)pathway.However,the role of dietary nitrate on the senescence-related decline in liver function is unclear.The findings of the present study showed that nitrate levels in the serum and liver decreased,whereas the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in serum increased in ageing mice.Consistently,cell senescence,decreased glycogen levels and increased lipid deposition were found in the liver of aged mice,both glucokinase(GCK)and phosphoenolpyruvate carboxykinase(PCK)were down-regulated(n=10).Daily nitrate intake(0.5 mmol L^(-1))restored nitrate levels,decreased ALT and AST levels,and prevented cell senescence and structural and glucose and lipid metabolism degeneration in liver tissue both in D-galactose(D-gal)-induced ageing mice(n=10)and in natural aged mice(n=10).In conclusion,the present study demonstrated that the reduction of nitrate levels was correlated with liver degeneration in ageing individuals and that dietary supplement of nitrate could restore the nitrate levels in serum and the liver and prevent ageing-related liver degeneration.

关键词：肝功能硝酸盐衰落无机调查结果并发症治疗学氧化物

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Mandible exosomal ssc-mir-133b regulates tooth development in miniature swine via endogenous apoptosis

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Bone Research 2018年第4期6卷 408-417页

作者： Ye Li Xinxin Wang Jiali Ren Xiaoshan Wu Guoqing Li Zhipeng Fan Chunmei Zhang Ang Li Songlin Wang Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Key laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of Stomatology Xi'an Jiaotong University laboratory of molecular Signaling and Stem Cell therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University Department of Biochemistry and molecular Biology Capital Medical University School of Basic Medical Sciences

Signal transduction between different organs is crucial in the normal development of the human body. As an important medium for signal communication, exosomes can transfer important information, such as microRNAs(miRNAs), from donors to receptors.MiRNAs are known to fine-tune a variety of biological processes, including maxillofacial development; however, the underlying mechanism remains largely unknown. In the present study, transient apoptosis was found to be due to the expression of a miniature swine maxillofacial-specific miRNA, ssc-mir-133b. Upregulation of ssc-mir-133b resulted in robust apoptosis in primary dental mesenchymal cells in the maxillofacial region. Cell leukemia myeloid 1(Mcl-1) was verified as the functional target, which triggered further downstream activation of endogenous mitochondria-related apoptotic processes during tooth development.More importantly, mandible exosomes were responsible for the initial apoptosis signal. An animal study demonstrated that ectopic expression of ssc-mir-133 b resulted in failed tooth formation after 12 weeks of subcutaneous transplantation in nude mice. The tooth germ developed abnormally without the indispensable exosomal signals from the mandible.

关键词： Mandible Signal miRNAs

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Specific RNA m6A modification sites in bone marrow mesenchymal stem cells from the jawbone marrow of type 2 diabetes patients with dental implant failure

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International Journal of Oral Science 2023年第1期15卷 50-62页

作者： Wanhao Yan Xiao Lin Yiqian Ying Jun Li Zhipeng Fan laboratory of molecular Signaling and Stem Cells therapy Beijing Key Laboratory of Tooth Regeneration and Function ReconstructionCapital Medical University School of StomatologyBeijingChina Department of Dental Implant Center Beijing Stomatological HospitalSchool of StomatologyCapital Medical UniversityBeijingChina Department of Oral Implantology Tianjin Stomatological HospitalSchool of MedicineNankai UniversityTianjinChina Research Unit of tooth Development and regeneration Chinese Academy of Medical SciencesBeijingChina

The failure rate of dental implantation in patients with well-controlled type 2 diabetes mellitus(T2DM)is higher than that in nondiabetic patients.This due,in part,to the impaired function of bone marrow mesenchymal stem cells(BMSCs)from the jawbone marrow of T2DM patients(DM-BMSCs),limiting implant osseointegration.RNA N6-methyladenine(m6A)is important for BMSC function and diabetes regulation.However,it remains unclear how to best regulate m6A modifications in DM-BMSCs to enhance function.Based on the“m6A site methylation stoichiometry”of m6A single nucleotide arrays,we identified 834 differential m6Amethylated genes in DM-BMSCs compared with normal-BMSCs(N-BMSCs),including 43 and 790 m6A hypermethylated and hypomethylated genes,respectively,and 1 gene containing hyper-and hypomethylated m6A sites.Differential m6A hypermethylated sites were primarily distributed in the coding sequence,while hypomethylated sites were mainly in the 3’-untranslated region.The largest and smallest proportions of m6A-methylated genes were on chromosome 1 and 21,respectively.Maz F-PCR and real-time RTPCR results for the validation of erythrocyte membrane protein band 4.1 like 3,activity-dependent neuroprotector homeobox(ADNP),growth differentiation factor 11(GDF11),and regulator of G protein signalling 2 agree with m6A single nucleotide array results;ADNP and GDF11 m RNA expression decreased in DM-BMSCs.Furthermore,gene ontology and Kyoto Encyclopedia of genes and Genomes analyses suggested that most of these genes were enriched in metabolic processes.This study reveals the differential m6A sites of DM-BMSCs compared with N-BMSCs and identifies candidate target genes to enhance BMSC function and improve implantation success in T2DM patients.

关键词： patients impaired implantation

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Extracellular matrix protein and gene evolution during cap and bell stage of developing deciduous tooth in miniature pigs

Extracellular matrix protein and gene evolution during cap a...

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2017全国口腔生物医学学术年会

作者： Yang Li Xiaoshan Wu Li Yan Yiyi Gong Zhifang Wu Fu Wang Junqi He Haiteng Deng Songlin Wang Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction School of Stomatology Capital Medical University MOE Key laboratory of Bioinformatics School of Life Sciences Tsinghua University Department of Biochemistry and molecular Biology Capital Medical University School of Basic Medical Science

Objectives:The extracellular matrix(ECM)of the tooth germ performs an important role in growth regulation,differentiation and organization of tooth germ.The natural tooth ECM composition was partially assessed using h...

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MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1

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International Journal of Oral Science 2023年第4期15卷 649-663页

作者： Chen Zhang Weilong Ye Mengyao Zhao Lujue Long Dengsheng Xia Zhipeng Fan laboratory of molecular Signaling and Stem Cells therapy Beijing Key Laboratory of Tooth Regeneration and Function ReconstructionBeijing Stomatological HospitalSchool of StomatologyCapital Medical UniversityBeijingChina Department of Dental Emergency Beijing Stomatological HospitalSchool of StomatologyCapital Medical UniversityBeijingChina Beijing laboratory of Oral Health Capital Medical UniversityBeijingChina Research Unit of tooth Development and regeneration Chinese Academy of Medical SciencesBeijingChina

Mesenchymal stem cell(MSC)-based therapy has emerged as a promising treatment for spinal cord injury(SCI),but improving the neurogenic potential of MSCs remains a challenge.Mixed lineage leukemia 1(MLL1),an H3K4me3 methyltransferases,plays a critical role in regulating lineage-specific gene expression and influences neurogenesis.In this study,we investigated the role and mechanism of MLL1 in the neurogenesis of stem cells from apical papilla(SCAPs).We examined the expression of neural markers,and the nerve repair and regeneration ability of SCAPs using dynamic changes in neuron-like cells,immunofluorescence staining,and a SCI model.We employed a coimmunoprecipitation(Co-IP)assay,real-time RT-PCR,microarray analysis,and chromatin immunoprecipitation(ChIP)assay to investigate the molecular mechanism.The results showed that MLL1 knock-down increased the expression of neural markers,including neurogenic differentiation factor(NeuroD),neural cell adhesion molecule(NCAM),tyrosine hydroxylase(TH),βIII-tubulin and Nestin,and promoted neuron-like cell formation in SCAPs.In vivo,a transplantation experiment showed that depletion of MLL 1 in SCAPs can restore motor function in a rat SCI model.MLL1 can combine with WD repeat domain 5(WDR5)and WDR5 inhibit the expression of neural markers in SCAPs.MLL1 regulates Hairy and enhancer of split 1(HES1)expression by directly binds to HES1 promoters via regulating H3K4me3 methylation by interacting with WDR5.Additionally,HES1 enhances the expression of neural markers in SCAPs.Our findings demonstrate that MLL1 inhibits the neurogenic potential of SCAPs by interacting with WDR5 and repressing HES1.These results provide a potential therapeutic target for promoting the recovery of motor function in SCI patients.

关键词： HES1 neurogenic MLL1

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SCAPs Regulate Differentiation of DFSCs During tooth Root Development in Swine

SCAPs Regulate Differentiation of DFSCs During Tooth Root De...

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2018全国口腔生物医学学术年会

作者： Xiaoshan Wu Lei Hu Yan Li Yang Li Fu Wang Ping Ma Jinsong Wang Chunmei Zhang Canhua Jiang Songlin Wang Department of Oral and Maxillofacial Surgery Xiangya Hospital Central South University Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Department of Oral Basic Science School of Stomatology Dalian Medical University

Objective: The tooth root transmits and balances occlusal forces through the periodontium to the alveolar bone. The periodontium, including the gingiva, the periodontal ligament, the cementum and the partial alveolar bone, derives from the dental follicle(DF), except for the gingiva. In the early developmental stages, the DF surrounds the tooth germ as a sphere and functions to promote tooth eruption. However, the morphological dynamics and factors regulating the differentiation of the DF during root elongation remain largely unknown. Methods: Miniature pigs are regarded as a useful experimental animal for modeling in craniofacial research because they are similar to humans with respect to dentition and mandible anatomy. In the present study, we used the third deciduous incisor of miniature pig as the model to investigate the factors influencing DF differentiation during root development. Results: We found that the DF was shaped like a crescent and was located between the root apical and the alveolar bone. The expression levels of WNT5a, β-Catenin, and COL-I gradually increased from the center of the DF(beneath the apical foramen) to the lateral coronal corner, where the DF differentiates into the periodontium. To determine the potential regulatory role of the apical papilla on DF cell differentiation, we co-cultured dental follicle stem cells(DFSCs) with stem cells of the apical papilla(SCAPs). The osteogenesis and fibrogenesis abilities of DFSCs were inhibited when being co-cultured with SCAPs, suggesting that the fate of the DF can be regulated by signals from the apical papilla. The apical papilla may sustain the undifferentiated status of DFSCs before root development finishes. Conclusion: These data yield insight into the interaction between the root apex and surrounding DF tissues in root and periodontium development and shed light on the future study of root regeneration in large mammals.

关键词： tooth root root apex dental sac regeneration mammals Sus scrofa

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人源间充质干细胞药物的研发和转化应用

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Science Bulletin 2023年第9期68卷 860-863页

作者：刘怡 Dana T.Graves 王松灵 laboratory of Tissue regeneration and Immunology and Department of Periodontics Beijing Key Laboratory of Tooth Regeneration and Function ReconstructionSchool of StomatologyCapital Medical UniversityBeijing 100050China Beijing laboratory of Oral Health Capital Medical UniversityBeijing 100069China Department of Periodontics School of Dental MedicineUniversity of PennsylvaniaPhiladelphia PA 19104USA Department of Biochemistry and molecular Biology School of Basic Medical SciencesCapital Medical UniversityBeijing 100069China

In recent years,mesenchymal stem cells(MSCs)have been widely applied in the treatment of various clinical diseases because of multiple advantages and significant therapeutic effects.Despite the long research time and complicated approval procedures,MSC therapy has been gradually progressing and gaining popularity worldwide,including in China.

关键词：间充质干细胞 clinical diseases

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