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Cell membrane vesicles derived from hBMSCs and hUVECs enhance bone regeneration

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Bone Research 2024年第2期12卷 361-371页

作者： Dandan Wang Yaru Guo boon Chin heng Xuehui Zhang Yan Wei Ying He Mingming Xu Bin Xia Xuliang Deng Department of Pediatric Dentistry Peking University School and Hospital of StomatologyBeijing 100081P.R.China Department of Geriatric Dentistry Peking University School and Hospital of StomatologyNational Center for StomatologyNational Clinical Research Center for Oral DiseasesNational Engineering Research Center of Oral Biomaterials and Digital Medical DevicesBeijing 100081P.R.China Department of Dental Materials&Dental Medical Devices Testing Center Peking University School and Hospital of StomatologyNational Engineering Research Center of Oral Biomaterials and Digital Medical DevicesBeijing 100081P.R.China

Bone tissue renewal can be enhanced through co-transplantation of bone mesenchymal stem cells(BMSCs)and vascular endothelial cells(ECs).However,there are apparent limitations in stem cell-based therapy which hinder its clinic ***,we investigated the potential of alternative stem cell substitutes for facilitating bone *** this study,we successfully prepared cell membrane vesicles(CMVs)from BMSCs and *** results showed that BMSC-derived cell membrane vesicles(BMSC-CMVs)possessed membrane receptors involved in juxtacrine signaling and growth factors derived from their parental ***-derived cell membrane vesicles(EC-CMVs)also contained BMP2 and VEGF derived from their parental ***-CMVs enhanced tube formation and migration ability of hUVECs,while EC-CMVs promoted the osteogenic differentiation of hBMSCs in *** a rat skull defect model,we found that co-transplantation of BMSC-CMVs and EC-CMVs could stimulate angiogenesis and bone formation in ***,our research might provide an innovative and feasible approach for cell-free therapy in bone tissue regeneration.

关键词： hinder apparent vesicles

Extrapolating neurogenesis of mesenchymal stem/stromal cells on electroactive and electroconductive scaffolds to dental and oral-derived stem cells

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International Journal of Oral Science 2022年第2期14卷 123-131页

作者： boon Chin heng Yunyang Bai Xiaochan Li Xuehui Zhang Xuliang Deng Central Laboratory Peking University School and Hospital of StomatologyBeijingChina School of Medical and Life Sciences Sunway UniversitySubang JayaSelangor Darul EhsanMalaysia Department of Geriatric Dentistry Peking University School and Hospital of StomatologyBeijingChina Department of Dental Materials&Dental Medical Devices Testing Center Peking University School and Hospital of StomatologyBeijingChina National Engineering Laboratory for Digital and Material Technology of Stomatology NMPA Key Laboratory for Dental MaterialsBeijing Laboratory of Biomedical Materials&Beijing Key Laboratory of Digital StomatologyPeking University School and Hospital of StomatologyBeijingChina

The high neurogenic potential of dental and oral-derived stem cells due to their embryonic neural crest origin,coupled with their ready accessibility and easy isolation from clinical waste,make these ideal cell sources for neuroregeneration ***,these cells also have high propensity to differentiate into the osteo-odontogenic *** strategy to enhance neurogenesis of these cells may be to recapitulate the natural physiological electrical microenvironment of neural tissues via electroactive or electroconductive tissue engineering ***,to date,there had been hardly any such studies on these *** relevant scientific information comes from neurogenesis of other mesenchymal stem/stromal cell lineages(particularly bone marrow and adipose tissue)cultured on electroactive and electroconductive scaffolds,which will therefore be the focus of this *** there are larger number of similar studies on neural cell lines(***12),neural stem/progenitor cells,and pluripotent stem cells,the scientific data from such studies are much less relevant and less translatable to dental and oral-derived stem cells,which are of the mesenchymal *** extrapolation work is needed to validate that electroactive and electroconductive scaffolds can indeed promote neurogenesis of dental and oral-derived stem cells,which would thus facilitate clinical applications in neuroregeneration therapy.

关键词： mesenchymal conductive neural

Metformin can mitigate skeletal dysplasia caused by Pck2 deficiency

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International Journal of Oral Science 2022年第4期14卷 572-583页

作者： Zheng Li Muxin Yue boon Chin heng Yunsong Liu Ping Zhang Yongsheng Zhou Department of Prosthodontics Peking University School and Hospital of StomatologyBeijingChina National Center of Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices&Beijing Key Laboratory of Digital Stomatology 22 Zhongguancun South AvenueHaidian DistrictBeijingChina The Central Laboratory Peking University School and Hospital of StomatologyBeijingChina

As an important enzyme for gluconeogenesis, mitochondrial phosphoenolpyruvate carboxykinase(PCK2) has further complex functions beyond regulation of glucose metabolism. Here, we report that conditional knockout of Pck2 in osteoblasts results in a pathological phenotype manifested as craniofacial malformation, long bone loss, and marrow adipocyte accumulation. Ablation of Pck2 alters the metabolic pathways of developing bone, particularly fatty acid metabolism. However, metformin treatment can mitigate skeletal dysplasia of embryonic and postnatal heterozygous knockout mice, at least partly via the AMPK signaling ***, these data illustrate that PCK2 is pivotal for bone development and metabolic homeostasis, and suggest that regulation of metformin-mediated signaling could provide a novel and practical strategy for treating metabolic skeletal dysfunction.

关键词： skeletal dysplasia homeostasis

Nanosecond pulsed electric fields prime mesenchymal stem cells to peptide ghrelin and enhance chondrogenesis and osteochondral defect repair in vivo

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Science China(Life Sciences) 2022年第5期65卷 927-939页

作者： Kejia Li Litong Fan Jianjing Lin boon Chin heng Zhantao Deng Qiujian Zheng Jue Zhang Yangzi Jiang Zigang Ge Department of Biomedical Engineering College of EngineeringPeking UniversityBeijing 100871China Arthritis Clinical and Research Center Peking University People’s HospitalBeijing 100044China Arthritis Institute Peking UniversityBeijing 100871China Peking University School of Stomatology Beijing 100081China Department of Orthopedics Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080China Institute of Biomechanics and Biomedical Engineering College of EngineeringPeking UniversityBeijing 100871China Institute for Tissue Engineering and Regenerative Medicine School of Biomedical SciencesFaculty of MedicineThe Chinese University of Hong KongHong Kong 999077China School of Biomedical Sciences Faculty of MedicineThe Chinese University of Hong KongHong Kong 999077China Department of Biomedical Engineering College of Future TechnologyPeking UniversityBeijing 100871China

Mesenchymal stem cells(MSCs) are important cell sources in cartilage tissue development and homeostasis,and multiple strategies have been developed to improve MSCs chondrogenic differentiation with an aim of promoting cartilage *** we report the effects of combining nanosecond pulsed electric fields(ns PEFs) followed by treatment with ghrelin(a hormone that stimulates release of growth hormone) to regulate chondrogenesis of *** PEFs and ghrelin were observed to separately enhance the chondrogenesis of MSCs,and the effects were significantly enhanced when the bioelectric stimulation and hormone were combined,which in turn improved osteochondral tissue repair of these cells within Sprague Dawley *** further found that ns PEFs can prime MSCs to be more receptive to subsequent stimuli of differentiation by upregulated Oct4/Nanog and activated JNK signaling *** initiated chondrogenic differentiation by activation of ERK1/2 signaling pathway,and RNA-seq results indicated 243 genes were regulated,and JAK-STAT signaling pathway was ***,the sequential order of applying these two stimuli is critical,with ns PEFs pretreatment followed by ghrelin enhanced chondrogenesis of MSCs in vitro and subsequent cartilage regeneration in vivo,but not vice *** synergistic prochondrogenic effects provide us new insights and strategies for future cell-based therapies.

关键词： mesenchymal stem cells nanosecond pulsed electric fields ghrelin chondrogenic differentiation

Electrical charge on ferroelectric nanocomposite membranes enhances SHED neural differentiation

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Bioactive Materials 2023年第2期20卷 81-92页

作者： Xiaochan Li boon Chin heng Yunyang Bai Qianqian Wang Min Gao Ying He Xinwen Zhang Xuliang Deng Xuehui Zhang Department of Geriatric Dentistry Peking University School and Hospital of StomatologyBeijing100081PR China Department of Dental Materials&Dental Medical Devices Testing Center Peking University School and Hospital of StomatologyBeijing100081PR China Department of Prosthodontics Peking University School and Hospital of StomatologyBeijing100081PR China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081PR China Center of Implant Dentistry School and Hospital of StomatologyChina Medical UniversityLiaoning Provincial Key Laboratory of Oral DiseasesShenyang110002PR China National Engineering Research Center of Oral Biomaterials and Digital Medical Devices NMPA Key Laboratory for Dental MaterialsBeijing Laboratory of Biomedical MaterialsPeking University School and Hospital of StomatologyBeijing100081PR China

Stem cells from human exfoliated deciduous teeth(SHED)uniquely exhibit high proliferative and neurogenic *** biomaterials have been demonstrated to promote neural differentiation of stem cells,but the dose-response effect of electrical stimuli from these materials on neural differentiation of SHED remains to be ***,by utilizing different annealing temperatures prior to corona poling treatment,BaTiO_(3)/P(VDF-TrFE)ferroelectric nanocomposite membranes with varying charge polarization intensity(d_(33)≈0,4,12 and 19 pC N^(-1))were *** expression of neural markers,increased cell elongation and more prominent neurite outgrowths were observed with increasing surface charge of the nanocomposite membrane indicating a dose-response effect of surface electrical charge on SHED neural *** investigations of the underlying molecular mechanisms revealed that intracellular calcium influx,focal adhesion formation,FAK-ERK mechanosensing pathway and neurogenic-related ErbB signaling pathway were implicated in the enhancement of SHED neural differentiation by surface electrical ***,this study confirms the dose-response effect of biomaterial surface charge on SHED neural differentiation and provides preliminary insights into the molecular mechanisms and signaling pathways involved.

关键词： Surface charge Electric polarization Dose-response effect Electrical microenvironment Neurogenesis

The bioelectrical properties of bone tissue

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Animal Models and Experimental Medicine 2023年第2期6卷 120-130页

作者： boon Chin heng Yunyang Bai Xiaochan Li Yanze Meng Yanhui Lu Xuehui Zhang Xuliang Deng Department of Dental Materials&Dental Medical Devices Testing Center Peking University School and Hospital of StomatologyBeijingPR China Central Laboratory Peking University School and Hospital of StomatologyBeijingPR China School of Medical and Life Sciences Sunway UniversitySubang JayaMalaysia Department of Geriatric Dentistry Peking University School and Hospital of StomatologyBeijingPR China National Engineering Research Center of Oral Biomaterials and Digital Medical Devices NMPA Key Laboratory for Dental MaterialsBeijing Laboratory of Biomedical Materials&Beijing Key Laboratory of Digital StomatologyPeking University School and Hospital of StomatologyBeijingPeople's Republic of China

Understanding the bioelectrical properties of bone tissue is key to developing new treatment strategies for bone diseases and injuries,as well as improving the design and fabrication of scaffold implants for bone tissue *** bioelectrical properties of bone tissue can be attributed to the interaction of its various cell lineages(osteocyte,osteoblast and osteoclast)with the surrounding extracellular matrix,in the presence of various biomechanical stimuli arising from routine physical activities;and is best described as a combination and overlap of dielectric,piezoelectric,pyroelectric and ferroelectric properties,together with streaming potential and *** is close interdependence and interaction of the various electroactive and electrosensitive components of bone tissue,including cell membrane potential,voltage-gated ion channels,intracellular signaling pathways,and cell surface receptors,together with various matrix components such as collagen,hydroxyapatite,proteoglycans and *** is the remarkably complex web of interactive cross-talk between the organic and non-organic components of bone that define its electrophysiological properties,which in turn exerts a profound influence on its metabolism,homeostasis and regeneration in health and *** has spurred increasing interest in application of electroactive scaffolds in bone tissue engineering,to recapitulate the natural electrophysiological microenvironment of healthy bone tissue to facilitate bone defect repair.

关键词： bone dielectric electric ferroelectric homeostasis metabolism piezoelectric pyroelectric regeneration

A novel gene-activated matrix composed of PEI/plasmid-BMP2 complexes and hydroxyapatite/chitosan-microspheres promotes bone regeneration

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Nano Research 2022年第7期15卷 6348-6360页

作者： Ruyuan Ding Yajun Liu Dawei Cheng Gang Yang Wenjing Wu Haoran Du Xin Jin Yihan Chen Yuanyin Wang boon Chin heng Qing Yang Jianguang XU Key Lab.of Oral Diseases Research of Anhui Province College&Hospital of StomatologyAnhui Medical UniversityHefei 230032China Central Laboratory Peking University School and Hospital of StomatologyBeijing 100081China School of Medical and Life Sciences Sunway UniversitySelangor Darul EhsanMalaysia Department of Orthopaedics The First Affiliated Hospital of Anhui Medical UniversityAnhui Medical UniversityHefei 230032China Department of Chemistry and Laboratory of Nanomaterials for Energy Conversion(LNEC)University of Science and Technology of China(USTC)Hefei 230026China

The incorporation of pro-osteogenic growth factors into bone graft materials to enhance bone regeneration is a key research area within the field of bone tissue engineering and regenerative ***,growth factors directly incorporated in protein form are easily degraded,and have a limited active half-life,which cannot exert long-term and stable osteoinductive and oteoconductive *** combination of gene therapy and tissue engineering through gene-activated matrix(GAM)may provide a good alternative solution to overcome such *** materials can be combined together with plasmid DNA and a chemical-based transfection agent to form GAM,through which transfected cells could secrete growth factors in a sustained manner over a longer time duration;thereby enabling bone graft materials to act as a repository of therapeutic genes,while providing structural support and a scaffold matrix for new bone tissue *** this study,we prepared hydroxyapatite/chitosan-microspheres(HA/CS-MS)with microfabrication technology and emulsification method,and loaded the polyethylene imine/bone morphogenetic protein 2 plasmid(PEI/pBMP2)complexes with high transfection capacity(transfection efficiency up to 54.79%±4.95%),thus forming a novel GAM system with superior bone regeneration capacity—PEI/pBMP2-HA/*** in vitro experiments in this study demonstrated that our GAM had excellent biocompatibility(with cell viability over 95%),and that the as-fabricated microsphere material possessed a nano-network fibrous structure similar to natural extracellular matrix(ECM),together with a higher surface area that can provide more cell adhesion *** sizes of the prepared microspheres were mainly distributed in the 160–180μm range,while the maximal loading rate of PEI-pBMP2 complexes was 59.79%±1.85%.As a loaded complexes system,the GAM can release plasmids in a slow controlled manner,effectively transfecting surrounding target cells(release effect for up to 21 d

关键词： BMP2 chitosan gene therapy nanoparticle regeneration microsphere

Matrix stiffness modulates tip cell formation through the p-PXN-Rac1-YAP signaling axis

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Bioactive Materials 2022年第1期7卷 364-376页

作者： Yaru Guo Feng Mei Ying Huang Siqin Ma Yan Wei Xuehui Zhang Mingming Xu Ying He boon Chin heng Lili Chen Xuliang Deng Department of Geriatric Dentistry Peking University School and Hospital of StomatologyBeijing100081China Department of Stomatology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430022China Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration Wuhan430022China Department of Dental Materials Peking University School and Hospital of StomatologyBeijing100081PR China National Engineering Laboratory for Digital and Material Technology of Stomatology Beijing100081PR China Beijing Laboratory of Biomedical Materials Peking University School and Hospital of StomatologyBeijing100081PR China Central Laboratory Peking University School and Hospital of StomatologyBeijing100081PR China

Endothelial tip cell outgrowth of blood-vessel sprouts marks the initiation of angiogenesis which is critical in physiological and pathophysiological ***,how mechanical characteristics of extracellular matrix(ECM)modulates tip cell formation has been largely *** this study,we found enhanced CD31 expression in the stiffening outer layer of hepatocellular carcinoma than in surrounding soft *** matrix promoted sprouting from endothelial cell(EC)spheroids and upregulated expressions of tip cell-enriched genes in ***,tip cells showed increased cellular stiffness,more actin cytoskeleton organization and enhanced YAP nuclear transfer than stalk and phalanx *** further uncovered that substrate stiffness regulates FAK and Paxillin phosphorylation in focal adhesion of ECs promoting Rac1 transition from inactive to active *** is subsequently activated and translocated into nucleus,leading to increased tip cell specification.p-Paxillin can also loosen the intercellular connection which also facilitates tip cell *** our present study shows that matrix stiffness modulates tip cell formation through p-PXN-Rac1-YAP signaling axis,shedding light on the role of mechanotransduction in tip cell *** is of special significance in biomaterial design and treatment of some pathological situations.

关键词： Tip cells Mechanotransduction Stiffness Angiogenesis Extracellular matrix

Free or fixed state of nHAP differentially regulates hBMSC morphology and osteogenesis through the valve role of ITGA7

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Bioactive Materials 2022年第12期7卷 539-551页

作者： Fangyuan Bao Junzhi Yi Yixiao Liu Yuliang Zhong Hui Zhang Zhonglin Wu boon Chin heng Ying Wang Ziyang Wang Lizi Xiao Hua Liu Hongwei Ouyang Jing Zhou Dr Li Dak Sum&Yip Yio Chin Center for Stem Cells and Regenerative Medicine and Department of Orthopedic Surgery of The Second Affiliated HospitalZhejiang University School of MedicineHangzhouPR China Department of Sports Medicine Zhejiang University School of MedicineHangzhouPR China Zhejiang University-University of Edinburgh Institute Zhejiang University School of Medicineand Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang ProvinceZhejiang University School of MedicineHangzhouPR China China Orthopedic Regenerative Medicine Group(CORMed) HangzhouPR China School of Stomatology Peking UniversityBeijingPR China Zhongshan School of Medicine Sun Yat-sen UniversityGuangzhouPR China

Nano-hydroxyapatite(nHAP)has been widely used in bone repair as an osteo-inductive and naturally-occurring ***,the optimal applied form of nHAP and the underlying mechanisms involved remain ***,to investigate into these,a range of corresponding models were designed,including three applied forms of nHAP(Free,Coating and 3D)that belong to two states(Free or fixed).The results indicate that when fixed nHAP was applied in the 3D form,optimal osteogenesis was induced in human bone marrow stem cells(hBMSCs)with increased bone volume via integrinα7(ITGA7)-mediated upregulation of the PI3K-AKT signaling pathway,while contrary results were observed with free *** osteogenesis experiments in mice subcutaneous transplantation model further confirmed the different tendencies of ITGA7 expression and osteogenesis of hBMSCs in free and fixed states of *** results revealed that the two states of nHAP play a different regulatory role in cell morphology and osteogenesis through the valve role of ITGA7,providing cues for better application of nanoparticles and a potential new molecular target in bone tissue engineering.

关键词： Applied forms nHAP Osteogenesis ITGA7