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Mesenchymal stem cell-derived Extracellular vesicles therapy in traumatic central nervous system diseases:a systematic review and meta-analysis

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Neural Regeneration Research 2023年第11期18卷 2406-2412页

作者： Zhelun Yang Zeyan Liang Jian Rao Fabin Lin Yike Lin Xiongjie Xu Chunhua Wang Chunmei Chen Department of Neurosurgery Fujian Medical University Union HospitalFuzhouFujian ProvinceChina

Although there are challenges in treating traumatic central nervous system diseases,mesenchymal stem cell-de rived Extracellular vesicles(MSC-EVs) have recently proven to be a promising non-cellular the rapy.We comprehensively evaluated the efficacy of mesenchymal stem cell-de rived Extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies.Our meta-analysis was registered at PROSPERO(CRD42022327904,May 24,2022).To fully retrieve the most relevant articles,the following databases were thoro ughly searched:PubMed,Web of Science,The Cochrane Library,and Ovid-Embase(up to April 1,2022).The included studies were preclinical studies of mesenchymal stem cell-derived Extracellular vesicles for traumatic central nervous system diseases.The Systematic Review Centre for Laboratory Animal Experimentation(SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies.After screening 2347studies,60 studies were included in this study.A meta-analysis was conducted for spinal co rd injury(n=52) and traumatic brain injury(n=8).The results indicated that mesenchymal stem cell-derived Extracellular vesicles treatment prominently promoted motor function recovery in spinal co rd injury animals,including rat Basso,Beattie and Bresnahan locomotor rating scale scores(standardized mean difference [SMD]:2.36,95% confidence interval [CI]:1.96-2.76,P Extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals,including the modified N eurological Severity Score(SMD=-4.48,95% CI:-6.12 to-2.84,P vesicles.For Basso,Bea

关键词： animals central nervous system diseases Extracellular vesicles mesenchymal stromal cell meta-analysis spinal cord injury traumatic brain injury

Orange-derived Extracellular vesicles nanodrugs for efficient treatment of ovarian cancer assisted by transcytosis effect

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Acta Pharmaceutica Sinica B 2023年第12期13卷 5121-5134页

作者： Feng Long Yao Pan Jinheng Li Suinan Sha Xiubo Shi Haoyan Guo Chuanqing Huang Qian Xiao Chao Fan Xingmei Zhang Jun-Bing Fan Ying Wang Cancer Research Institute Experimental Education/Administration CenterKey Laboratory of Functional Proteomics of Guangdong ProvinceSchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China Department of Neurobiology School of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China

Extracellular vesicles(EVs)have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size,biocompatibility,and high stability.Herein,we demonstrate orange-derived Extracellular vesicles(OEV)nanodrugs(DN@OEV)by modifying cRGD-targeted doxorubicin(DOX)nanoparticles(DN)onto the surface of OEV,enabling significantly enhancing tumor accumulation and penetration,thereby efficiently inhibiting the growth of ovarian cancer.The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells,which presented the average above 10-fold transcytosis effect compared with individual DN.It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway,thereby inducing the enhanced transcytosis.In particular,the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process.Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of thedrugdelivery system.

关键词： Extracellular vesicles Transcytosis Cancer treatment Drug delivery system Targeted modification Receptor-mediated endocytosis Intracellular trafficking Recycling endosome

Dual-engineered cartilage-targeting Extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis:Toward a precision therapy

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Bioactive Materials 2023年第12期30卷 169-183页

作者： Weixuan Liu Anqi Liu Xujun Li Ziyang Sun Zhenghua Sun Yaru Liu Gang Wang Dan Huang Hao Xiong Shiyang Yu Xintao Zhang Cunyi Fan Department of Sports Medicine Peking University Shenzhen HospitalShenzhen Peking University-The Hong Kong University of Science and Technology Medical CenterShenzhen518036China Shanghai Engineering Research Center for Orthopedic Material Innovation and Tissue Regeneration Shanghai201306China Department of Orthopedics Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200233China Department of Orthodontics Shanghai Stomatological Hospital&School of StomatologyFudan UniversityShanghai200001China Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases Fudan UniversityShanghai200001China Minhang Hospital Fudan UniversityShanghai201199China

Osteoarthritis(OA)is the most common disabling joint disease with no effective disease modifying drugs.Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models,representing a novel therapeutic strategy.In this study,we demonstrated that Extracellular vesicles derived from human umbilical cord mesenchymal stem cells(hUC-EVs)could maintain chondrocyte homeostasis and alleviate OA,and further revealed a novel molecular mechanism of this therapeutic effect.miR-223,which could directly bind with the 3′UTR of NLRP3 mRNA,was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting.For enhancing the effect on mitigating osteoarthritis,exogenous miR-223 was loaded into hUC-EVs by electroporation,and a collagen II-targeting peptide(WYRGRL)was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage.The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis,and offered excellent results for the treatment of OA.This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered Extracellular vesicles in OA treatment.

关键词： Osteoarthritis Extracellular vesicles NLRP3 inflammasome Pyroptosis Cartilage-targeting

Breakthrough of Extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

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Bioactive Materials 2023年第4期22卷 423-452页

作者： Zichang Liu Yu Zhuang Lianfei Fang Changyong Yuan Xudong Wang Kaili Lin Shanghai Ninth People’s Hospital Shanghai Jiao Tong University School of MedicineCollege of StomatologyShanghai Jiao Tong UniversityNational Center for StomatologyNational Clinical Research Center for Oral DiseasesShanghai Key Laboratory of StomatologyResearch Unit of Oral and Maxillofacial Regenerative MedicineChinese Academy of Medical SciencesShanghai200011China Shanghai Jiao Tong University School of Medicine Shanghai200025China Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration(Tongji University) Ministry of Education389 Xincun Road200065 ShanghaiPR China School of Stomatology Xuzhou Medical UniversityDepartment of Dental ImplantThe Affiliated Stomatological Hospital of Xuzhou Medical UniversityXuzhouChina

Osteoarthritis(OA)is a highly prevalent whole-joint disease that causes disability and pain and affects a patient’s quality of life.However,currently,there is a lack of effective early diagnosis and treatment.Although stem cells can promote cartilage repair and treat OA,problems such as immune rejection and tumorigenicity persist.Extracellular vesicles(EVs)can transmit genetic information from donor cells and mediate intercellular communication,which is considered a functional paracrine factor of stem cells.Increasing evidences suggest that EVs may play an essential and complex role in the pathogenesis,diagnosis,and treatment of OA.Here,we introduced the role of EVs in OA progression by influencing inflammation,metabolism,and aging.Next,we discussed EVs from the blood,synovial fluid,and joint-related cells for diagnosis.Moreover,we outlined the potential of modified and unmodified EVs and their combination with biomaterials for OA therapy.Finally,we discuss the deficiencies and put forward the prospects and challenges related to the application of EVs in the field of OA.

关键词： Extracellular vesicles Osteoarthritis Biomarkers Diagnosis Treatment

The miR-21-5p enriched in the apoptotic bodies of M2 macrophage-derived Extracellular vesicles alleviates osteoarthritis by changing macrophage phenotype

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Genes & Diseases 2023年第3期10卷 1114-1129页

作者： Leilei Qin Jianye Yang Xudong Su Xilan li Yiting Lei Lili Dong Hong Chen Cheng Chen Chen Zhao Huan Zhang Jun Deng Ning Hu Wei Huang Department of Orthopaedics The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Orthopedic Laboratory of Chongqing Medical University The First Affiliated Hospital of Chongqing Medical UniversityChongqing 400016China Institute of Burn Research Southwest HospitalState Key Lab of TraumaBurn and Combined InjuryArmy Medical UniversityChongqing 400038China

Macrophages (Mφs) play a crucial role in the pathological progression of osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs can alleviate OA-related inflammation and promote cartilage repair. Apoptosis is a natural process associated with tissue repair. A large number of apoptotic bodies (ABs), a type of extracellular vesicle, are produced during apoptosis, and this is associated with a reduction in inflammation. However, the functions of apoptotic bodies remain largely unknown. In this study, we investigated the role of M2-Mφs-derived apoptotic bodies (M2-ABs) in regulating the M1/M2 balance of macrophages in a mouse model of OA. Our data show that M2-ABs can be targeted for uptake by M1-Mφs, and this reprograms M1-to-M2 phenotypes within 24 h. The M2-ABs significantly ameliorated the severity of OA, alleviated the M1-mediated pro-inflammatory environment, and inhibited chondrocyte apoptosis in mice. RNA-seq revealed that M2-ABs were enriched with miR-21–5p, a microRNA that is negatively correlated with articular cartilage degeneration. Inhibiting the function of miR-21–5p in M1-Mφs significantly reduced M2-ABs-guided M1-to-M2 reprogramming following in vitro cell transfection. Together, these results suggest that M2-derived apoptotic bodies can prevent articular cartilage damage and improve gait abnormalities in OA mice by reversing the inflammatory response caused by M1 macrophages. The mechanism underlying these findings may be related to miR-21-5p-regulated inhibition of inflammatory factors. The application of M2-ABs may represent a novel cell therapy, and could provide a valuable strategy for the treatment of OA and/or chronic inflammation.

关键词： Apoptotic body Extracellular vesicles Macrophage phenotype switch Micr oRNA-21 Osteoarthritis

Small-Extracellular vesicles and their microRNA cargo from porcine follicular fluids:the potential association with oocyte quality

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Journal of Animal Science and Biotechnology 2022年第6期13卷 1727-1742页

作者： Ahmed Gad Matej Murin Alexandra Bartkova Veronika Kinterova Katerina Marcollova Jozef Laurincik Radek Prochazka Institute of Animal Physiology and Genetics Czech Academy of Sciences27721 LiběchovCzech Republic Department of Animal Production Faculty of AgricultureCairo UniversityGiza 12613Egypt Department of Botany and Genetics Faculty of Natural SciencesConstantine the Philosopher University in Nitra94901 NitraSlovakia.

Background: Ovarian follicular fluids(FFs) contain several kinds of regulatory factors that maintain a suitable micro-environment for oocyte development. Extracellular vesicles(EVs) are among the factors that play essential roles in regulating follicle and oocyte development through their cargo molecules that include microRNAs(miRNAs). This study aimed to investigate small-EV(s-EV) miRNAs in porcine FFs and their potential association with oocyte quality.Methods: Individual aspirated oocytes were stained with lissamine green B stain(LB), a vital stain for oocyte quality, and each oocyte was classified as high-quality(unstained;HQ) or low-quality(stained;LQ). FFs corresponding to oocytes were pooled together into HQ and LQ groups. Small-EVs were isolated from FFs, characterized, and their miRNA cargo was identified using the Illumina Nova Seq sequencing platform. Additionally, s-EVs from the HQ and LQ groups were utilized to investigate their effect on oocyte development after co-incubation during in vitro maturation.Results: A total of 19 miRNAs(including miR-125b, miR-193a-5p, and miR-320) were significantly upregulated, while 23(including miR-9, miR-206, and miR-6516) were downregulated in the HQ compared to the LQ group. Apoptosis, p53 signaling, and cAMP signaling were among the top pathways targeted by the elevated miRNAs in the HQ group while oocyte meiosis, gap junction, and TGF-beta signaling were among the top pathways targeted by the elevated miRNAs in the LQ group. The supplementation of small-EVs during maturation does not affect the oocyte developmental rates. However, LQ s-EVs increase the proportion of oocytes with homogeneous mitochondrial distribution and decrease the proportion of heterogeneous distribution.Conclusion: Our findings indicated that FF-EVs contain different miRNA cargos associated with oocyte quality and could affect the mitochondrial distribution patterns during oocyte maturation.

关键词： Extracellular vesicles Follicular fuids MiRNA Oocyte quality Porcine

Reduced graphene oxide-embedded nerve conduits loaded with bone marrow mesenchymal stem cell-derived Extracellular vesicles promote peripheral nerve regeneration

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Neural Regeneration Research 2023年第1期18卷 200-206页

作者： Wei Zhang Xing-Xing Fang Qi-Cheng Li Wei Pi Na Han Department of Orthopedics and Trauma Peking University People’s HospitalBeijingChina National Center for Trauma Medicine BeijingChina Central Laboratory Peking University People’s HospitalBeijingChina

We previously combined reduced graphene oxide(rGO)with gelatin-methacryloyl(GelMA)and polycaprolactone(PCL)to create an rGO-GelMA-PCL nerve conduit and found that the conductivity and biocompatibility were improved.However,the rGO-GelMA-PCL nerve conduits differed greatly from autologous nerve transplants in their ability to promote the regeneration of injured peripheral nerves and axonal sprouting.Extracellular vesicles derived from bone marrow mesenchymal stem cells(BMSCs)can be loaded into rGO-GelMA-PCL nerve conduits for repair of rat sciatic nerve injury because they can promote angiogenesis at the injured site.In this study,12 weeks after surgery,sciatic nerve function was measured by electrophysiology and sciatic nerve function index,and myelin sheath and axon regeneration were observed by electron microscopy,immunohistochemistry,and immunofluorescence.The regeneration of microvessel was observed by immunofluorescence.Our results showed that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived Extracellular vesicles were superior to rGO-GelMA-PCL conduits alone in their ability to increase the number of newly formed vessels and axonal sprouts at the injury site as well as the recovery of neurological function.These findings indicate that rGO-GelMA-PCL nerve conduits loaded with BMSC-derived Extracellular vesicles can promote peripheral nerve regeneration and neurological function recovery,and provide a new direction for the curation of peripheral nerve defect in the clinic.

关键词： angiogenesis axon bone mesenchymal stem cell Extracellular vesicles hybrid nanofibers myelin sheath nerve conduit neurological function peripheral nerve injury reduced graphene oxide

Extracellular vesicles derived from human dental mesenchymal stem cells stimulated with low-intensity pulsed ultrasound alleviate inflammation-induced bone loss in a mouse model of periodontitis

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Genes & Diseases 2023年第4期10卷 1613-1625页

作者： Tingwei Zhang Ziqi Chen Mengyuan Zhu Xuan Jing Xiaohui Xu Xulei Yuan Mengjiao Zhou Yanan Zhang Miao Lu Duanjing Chen Shihan Xu Jinlin Song Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences Chongqing Municipal Key Laboratory for Oral Biomedical Engineering of Higher Educationand Stomatological Hospital of Chongqing Medical UniversityChongqing 401147China

Extracellular vesicles(EVs)derived from mesenchymal stem cells(MSCs)have emerged as a new mode of intercellular crosstalk and are responsible for many of the thera-peutic effects of MSCs.To promote the application of MSC-EVs,recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities.The current paper details an optimization method using non-invasive low-intensity pulsed ul-trasound(LIPUS)as the stimulation for improving oral MSC-EV production and effectiveness.Stem cells from apical papilla(SCAP),a type of oral mesenchymal stem cell,displayed inten-sity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis.The stimuli increased the secretion of EVs by promoting the expres-sion of neutral sphingomyelinases in SCAP.In addition,EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of peri-odontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo.In addition,LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs.Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs.Taken together,these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV produc-tion and efficacy.

关键词： Extracellular vesicles Low-intensity pulsed ultrasound Oral bone loss Periodontitis Stem cells from apical papilla

Neutralization of SARS-CoV-2 pseudovirus using ACE2-engineered Extracellular vesicles

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1523-1533,F0004页

作者： Canhao Wu Qin Xu Huiyuan Wang Bin Tu Jiaxin Zeng Pengfei Zhao Mingjie Shi Hong Qiu Yongzhuo Huang Artemisinin Research Center First Clinical SchoolGuangzhou University of Chinese MedicineGuangzhou 510450China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Zhongshan Institute for Drug Discovery SIMMCASZhongshan 528437China Center of Clinical Pharmacology The Second Affiliated Hospital of Zhejiang UniversitySchool of MedicineHangzhou 310009China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China Taizhou University School of Advanced StudyInstitute of Natural Medicine and Health ProductTaizhou 318000China

The spread of coronavirus disease 2019(COVID-19)throughout the world has resulted in stressful healthcare burdens and global health crises.Developing an effective measure to protect people from infection is an urgent need.The blockage of interaction between angiotensin-converting enzyme 2(ACE2)and S protein is considered an essential target for anti-severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)drugs.A full-length ACE2 protein could be a potential drug to block early entry of SARS-Co V-2 into host cells.In this study,a therapeutic strategy was developed by using Extracellular vesicles(EVs)with decoy receptor ACE2 for neutralization of SARS-Co V-2.The EVs embedded with engineered ACE2(EVs-ACE2)were prepared;the EVs-ACE2 were derived from an engineered cell line with stable ACE2 expression.The potential effect of the EVs-ACE2 on anti-SARS-Co V-2 was demonstrated by both in vitro and in vivo neutralization experiments using the pseudovirus with the S protein(S-pseudovirus).EVs-ACE2 can inhibit the infection of S-pseudovirus in various cells,and importantly,the mice treated with intranasal administration of EVs-ACE2 can suppress the entry of S-pseudovirus into the mucosal epithelium.Therefore,the intranasal EVs-ACE2 could be a preventive medicine to protect from SARS-Co V-2 infection.This EVs-based strategy offers a potential route to COVID-19 drug development.

关键词： SARS-CoV-2 COVID-19 Spike protein Pseudovirus Extracellular vesicles ACE2 Intranasal administration Neutralization