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Bioorthogonal microglia-inspired mesenchymal stem cell bioengineering system creates livable niches for enhancing ischemic stroke recovery via the hormesis

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1412-1427页

作者： Jianpei Xu Yinzhe Sun Yang You Yuwen Zhang Dan Huang Songlei Zhou Yipu Liu Shiqiang Tong Fenfen Ma Qingxiang Song Chengxiang Dai Suke Li Jigang Lei Zhihua Wang Xiaoling Gao Jun Chen Shanghai Pudong Hospital&Department of Pharmaceutics School of PharmacyFudan UniversityShanghai 201203China Key Laboratory of Smart Drug Delivery Ministry of EducationSchool of PharmacyFudan UniversityShanghai 201203China Department of Pharmacology and Chemical Biology State Key Laboratory of Oncogenes and Related GenesShanghai Universities Collaborative Innovation Center for Translational MedicineShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Emergency Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Institute of Science and Technology for Brain-Inspired Intelligence&Department of Neurology Fudan UniversityShanghai 201203China Department of Rehabilitation Medicine Huashan HospitalFudan UniversityShanghai 201203China Daxing Research Institute University of Science and Technology BeijingBiomedical Industry BaseZhongguancun Science and Technology ParkBeijing 102600China cellular Biomedicine Group Inc. Shanghai 201210China

mesenchymal stem cells(MSCs)experience substantial viability issues in the stroke infarct region,limiting their therapeutic efficacy and clinical translation.High levels of deadly reactive oxygen radicals(ROS)and proinflammatory cytokines(PC)in the infarct milieu kill transplanted MSCs,whereas low levels of beneficial ROS and PC stimulate and improve engrafted MSCs’viability.Based on the intrinsic hormesis effects in cellular biology,we built a microglia-inspired MSC bioengineering system to transform detrimental high-level ROS and PC into vitality enhancers for strengthening MSC therapy.This system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective layer.In this system,extracellular ROSscavenging and PC-absorbing layers effectively buffer the deleterious effects and establish a microlivable niche at the level of a single MSC for transplantation.Meanwhile,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate healing.The engineered MSCs achieved viability five times higher than natural MSCs at seven days after transplantation and exhibited a superior therapeutic effect for stroke recovery up to 28 days.This vitality-augmented system demonstrates the potential to accelerate the clinical translation of MSC treatment and boost stroke recovery.

关键词： Ischemic stroke mesenchymal stem cell cell engineering Hormesis effect Bioorthogonal chemistry Microglia Reactive oxygen spices Proinflammatory cytokines

mesenchymal stem cell-and extracellular vesicle-based therapies for Alzheimer's disease:progress,advantages,and challenges

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Neural Regeneration Research 2023年第8期18卷 1645-1651页

作者： Renata Guedes de Jesus Gonçalves Juliana Ferreira Vasques Almir Jordão da Silva-Junior Fernanda Gubert Rosalia Mendez-Otero Instituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de JaneiroRio de JaneiroBrazil Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa Rio de JaneiroBrazil Plataformas Inovadoras em Terapias Avançadas Departamento de Ciência e Tecnologia-Ministério da Saúde(DECIT-MS)Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq)Brazil Programa Redes de Pesquisa em Saúde no Estado do Rio de Janeiro Rio de JaneiroBrazil Instituto de Ciências Biomédicas Universidade Federal do Rio de JaneiroRio de JaneiroBrazil Programa Redes de Pesquisa em Nanotecnologia no Estado do Rio de Janeiro Rio de JaneiroBrazil

Alzheimer's disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer's disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer's disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer's disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

关键词： Alzheimer's disease amyloid-β cell therapy cell transplantation exosomes extracellular vesicles mesenchymal stem cell micro vesicles neuroinflammation tau protein

mesenchymal stem cell-derived exosomes regulate microglia phenotypes:a promising treatment for acute central nervous system injury

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Neural Regeneration Research 2023年第8期18卷 1657-1665页

作者： Yu-Yan Liu Yun Li Lu Wang Yan Zhao Rui Yuan Meng-Meng Yang Ying Chen Hao Zhang Fei-Hu Zhou Zhi-Rong Qian Hong-Jun Kang Medical School of Chinese PLA BeijingChina Department of Critical Care Medicine the First Medical CenterChinese PLA General HospitalBeijingChina Beidou Precision Medicine Insititute GuangzhouGuangdong ProvinceChina

There is growing evidence that long-term central nervous system(CNS)inflammation exacerbates secondary deterioration of brain structures and functions and is one of the major determinants of disease outcome and progression.In acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and regeneration.However,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual role.mesenchymal stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative properties.MSC-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and prognosis.MSC-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical potential.This review summarized the classification of acute CNS injury disorders and discussed the prominent role of microglial activation in acute CNS inflammation and the specific role of MSC-Exos in regulating pro-inflammatory microglia in neuroinflammatory repair following acute CNS injury.Finally,this review explored the potential mechanisms and factors associated with MSCExos in modulating the phenotypic balance of microglia,focusing on the interplay between CNS inflammation,the brain,and injury aspects,with an emphasis on potential strategies and therapeutic interventions for improving functional recovery from early CNS inflammation caused by acute CNS injury.

关键词： acute CNS injury central nervous system inflammation exosome immune regulation mesenchymal stem cell mesenchymal stem cell-derived exosomes(MSC-Exos) microglia activation microglia phenotypic transformation molecular mechanism neuroinflammation

mesenchymal stem cell-derived exosome:The likely game-changer in stem cell research

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BIOcell 2022年第5期46卷 1169-1172页

作者： DICKSON KOFI WIREDU OCANSEY XINWEI XU LU ZHANG FEI MAO Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province School of MedicineJiangsu UniversityZhenjiangChina Directorate of University Health Services University of Cape CoastCape CoastGhana

stem cell research is a promising area of transplantation and regenerative medicine with tremendous potential for improving the clinical treatment and diagnostic options across a variety of conditions and enhancing understanding of human development.Over the past few decades,mesenchymal stem cell(MSCs)studies have exponentially increased with a promising outcome.However,regardless of the huge investment and the research attention given to stem cell research,FDA approval for clinical use is still lacking.Amid the challenges confronting stem cell research as a cellbased product,there appears to be evidence of superior effect and heightened potential success in its expressed vesicles,exosomes,as cell-free products.In addition to their highly desirable intrinsic biologically unique structural,compositional,and morphological characteristics,as well as predominant physiochemical stability and biocompatibility properties,exosomes can also be altered to enhance their therapeutic capability or diagnostic imaging potential via physical,chemical,and biological modification approaches.More importantly,the powerful therapeutic potential and superior biological functions of exosomes,particularly,regarding engineered exosomes as cell-free products,and their utilization in a new generation of nanomedicine treatment,vaccination,and diagnosis platforms,brings hope of a change in the near future.This viewpoint discusses the trend of stem cell research and why stem cell-derived exosomes could be the game-changer.

关键词： mesenchymal stem cell Exosome cell-free therapy Regenerative medicine

Delivery of coenzyme Q10 loaded micelle targets mitochondrial ROS and enhances efficiency of mesenchymal stem cell therapy in intervertebral disc degeneration

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Bioactive Materials 2023年第5期23卷 247-260页

作者： Junyuan Sun Fei Yang Lianlei Wang Haichao Yu Zhijie Yang Jingjing Wei Krasimir Vasilev Xuesong Zhang Xinyu Liu Yunpeng Zhao Department of Orthopaedics Qilu HospitalCheeloo College of MedicineShandong UniversityJinanShandong250012PR China School of Pharmaceutical Sciences Shandong UniversityJinanShandong250012PR China School of Medicine Nankai UniversityTianjin300071PR China Department of Orthopaedics The Fourth Medical CentreChinese People’s Liberation Army General HospitalBeijing100048PR China Key Laboratory of Colloid and Interface Chemistry Ministry of EducationSchool of Chemistry and Chemical EngineeringShandong UniversityJinanShandong250100PR China Academic Unit of stem University of South AustraliaMawson LakesAdelaide5095South AustraliaAustralia College of Medicine and Public Health Flinders UniversityBedford Park5042South AustraliaAustralia

stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration(IVDD).However,the elevation of oxidative stress in the degenerated region impairs the efficiency of mesenchymal stem cells(BMSCs)transplantation treatment via exaggeration of mitochondrial ROS and promotion of BMSCs apoptosis.Herein,we applied an emulsion-confined assembly method to encapsulate Coenzyme Q10(Co-Q10),a promising hydrophobic antioxidant which targets mitochondria ROS,into the lecithin micelles,which renders the insoluble Co-Q10 dispersible in water as stable colloids.These micelles are injectable,which displayed efficient ability to facilitate Co-Q10 to get into BMSCs in vitro,and exhibited prolonged release of Co-Q10 in intervertebral disc tissue of animal models.Compared to mere use of Co-Q10,the Co-Q10 loaded micelle possessed better bioactivities,which elevated the viability,restored mitochondrial structure as well as function,and enhanced production of ECM components in rat BMSCs.Moreover,it is demonstrated that the injection of this micelle with BMSCs retained disc height and alleviated IVDD in a rat needle puncture model.Therefore,these Co-Q10 loaded micelles play a protective role in cell survival and differentiation through antagonizing mitochondrial ROS,and might be a potential therapeutic agent for IVDD.

关键词： Intervertebral disc degeneration Coenzyme Q10 mesenchymal stem cell Reactive oxygen species Micelle

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy

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药学学报:英文版 2023年第7期13卷 3027-3042页

作者： Luchen Sun Nanfei Yang Bing Chen Yuncheng Bei Zisheng Kang Can Zhang Nan Zhang Peipei Xu Wei Yang Jia Wei Jiangqiong Ke Weijian Sun Xiaokun Li Pingping Shen The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University Wenzhou 325027China School of Pharmaceutical Science Wenzhou Medical UniversityWenzhou 325035China Department of Urology Drum Tower HospitalMedical School of Nanjing UniversityInstitute of UrologyNanjing UniversityNanjing 210008China The Comprehensive Cancer Centre of Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing University Medical SchoolNanjing UniversityNanjing 210008China Department of Hematology the Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210093China State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases Center of Drug DiscoveryChina Pharmaceutical UniversityNanjing 210009China Centre of Micro/Nano Manufacturing Technology(MNMT-Dublin) School of Mechanical&Materials EngineeringUniversity College DublinDublin 4Ireland Department of Surgery Division of Cancer Biology and TherapeuticsCedars-Sinai Medical CenterLos AngelesCA 90048USA Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)&School of Pharmaceutical ScienceWenzhou Medical UniversityWenzhou 325035China Shenzhen Research Institute of Nanjing University Shenzhen 518000China

Currently the main treatment of acute myeloid leukemia(AML)is chemotherapy combining hematopoietic stem cell transplantation.However,the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice.Thus,there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects.Here,we revealed that umbilical cord-derived mesenchymal stem cells(UC-MSC)efficiently induced AML cell differentiation by shuttling the neutrophil elastase(NE)-packaged extracellular vesicles(EVs)into AML cells.Interestingly,the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor(VDR)activation in UC-MSC.Chemical activation of VDR by using its agonist 1a,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model.Based on these discoveries,to evade the risk of hypercalcemia,we synthetized and identified sw-22,a novel non-steroidal VDR agonist,which exerted a synergistic prodifferentiation function with UC-MSC on mitigating the progress of AML.Collectively,our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

关键词： mesenchymal stem cell Acute myeloid leukemia Extracellular vesicles Nonsteroidal VDR modulators Combination therapy

Epigenetic regulation of mesenchymal stem cell aging through histone modifications

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Genes & Diseases 2023年第6期10卷 2443-2456页

作者： Yanping Sun Haoyu Zhang Tao Qiu Li Liao Xiaoxia Su State Key Laboratory of Oral Diseases&National Clinical Research Center for Oral Diseases&Department of Pediatrics&Engineering Research Center of Oral Translational Medicine Ministry of EducationWest China Hospital of StomatologySichuan UniversityChengduSichuan 610041China

stem cell senescence and exhaustion,a hallmark of aging,lead to declines in tissue repair and regeneration in aged individuals.Emerging evidence has revealed that epigenetic regulation plays critical roles in the self-renew,lineage-commitment,survival,and function of stem cells.Moreover,epigenetic alterations are considered important drivers of stem cell dysfunction during aging.In this review,we focused on current knowledge of the histone modifications in the aging of mesenchymal stem cells(MSCs).The aberrant epigenetic modifications on histones,including methylation and acetylation,have been found in aging MSCs.By disturbing the expression of specific genes,these epigenetic modifications affect the self-renew,survival,and differentiation of MSCs.A set of epigenetic enzymes that write or erase these modifications are critical in regulating the aging of MSCs.Furthermore,we discussed the rejuvenation strategies based on epigenetics to prevent stem cell aging and/or rejuvenate senescent MSCs.

关键词： Aging Epigenetic Histone acetylation Histone methylation mesenchymal stem cell

Long non-coding RNA SNHG16 promotes human placenta-derived mesenchymal stem cell proliferation capacity through the PI3K/AKT pathway under hypoxia

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World Journal of stem cells 2022年第9期14卷 714-728页

作者： Xu-Dong Feng Jia-Hang Zhou Jun-Yao Chen Bing Feng Rui-Tian Hu Jian Wu Qiao-Ling Pan Jin-Feng Yang Jiong Yu Hong-Cui Cao State Key Laboratory for The Diagnosis and Treatment of Infectious Diseases National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina Department of Chemistry Duke UniversityDurhamNC 27708United States Jinan Microecological Biomedicine Shandong Laboratory Jinan 250117Shandong ProvinceChina Key Laboratory of Diagnosis and Treatment of Aging and Physic-chemical Injury Diseases of Zhejiang Province The First Affiliated HospitalZhejiang University School of MedicineHangzhou 310003Zhejiang ProvinceChina

BACKGROUND The effect of hypoxia on mesenchymal stem cells(MSCs)is an emerging topic in MSC biology.Although long non-coding RNAs(lncRNAs)and messenger RNAs(mRNAs)are reported to play a critical role in regulating the biological characteristics of MSCs,their specific expression and co-expression profiles in human placenta-derived MSCs(hP-MSCs)under hypoxia and the underlying mechanisms of lncRNAs in hP-MSC biology are unknown.AIM To reveal the specific expression profiles of lncRNAs in hP-MSCs under hypoxia and initially explored the possible mechanism of lncRNAs on hP-MSC biology.METHODS Here,we used a multigas incubator(92.5%N_(2),5%CO_(2),and 2.5%O_(2))to mimic the potential of hP-MSCs.RNA sequencing technology was applied to identify the exact expression profiles of lncRNAs and mRNAs under hypoxia.RESULTS We identified 289 differentially expressed lncRNAs and 240 differentially expressed mRNAs between the hypoxia and normoxia groups.Among them,the lncRNA SNHG16 was upregulated under hypoxia,which was also validated by reverse transcription-polymerase chain reaction.SNHG16 was confirmed to affect hP-MSC proliferation rates using a SNHG16 knockdown model.SNHG16 overexpression could significantly enhance the proliferation capacity of hP-MSCs,activate the PI3K/AKT pathway,and upregulate the expression of cell cycle-related proteins.CONCLUSION Our results revealed the specific expression characteristics of lncRNAs and mRNAs in hypoxiacultured hP-MSCs and that lncRNA SNHG16 can promote hP-MSC proliferation through the PI3K/AKT pathway.

关键词： Human placenta-derived mesenchymal stem cell Hypoxia Long non-coding RNAs Proliferation mesenchymal stem cell

Bone marrow mesenchymal stem cell-derived exosomal microRNAs target PI3K/Akt signaling pathway to promote the activation of fibroblasts

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World Journal of stem cells 2023年第4期15卷 248-267页

作者： Fang-Qi Li Wen-Bo Chen Zhi-Wen Luo Yi-Sheng Chen Ya-Ying Sun Xiao-Ping Su Jun-Ming Sun Shi-Yi Chen Department of Sports Medicine Huashan HospitalFudan UniversityShanghai 200040China Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina Laboratory Animal Center Guangxi Medical UniversityNanning 530021Guangxi Zhuang Autonomous RegionChina

BACKGROUND Fibroblast plays a major role in tendon-bone healing.Exosomes derived from bone marrow mesenchymal stem cells(BMSCs)can activate fibroblasts and promote tendon-bone healing via the contained microRNAs(miRNAs).However,the underlying mechanism is not comprehensively understood.Herein,this study aimed to identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets,and to verify their effects as well as mechanisms on fibroblasts.AIM To identify overlapped BMSC-derived exosomal miRNAs in three GSE datasets and verify their effects as well as mechanisms on fibroblasts.METHODS BMSC-derived exosomal miRNAs data(GSE71241,GSE153752,and GSE85341)were downloaded from the Gene Expression Omnibus(GEO)database.The candidate miRNAs were obtained by the intersection of three data sets.TargetScan was used to predict potential target genes for the candidate miRNAs.Functional and pathway analyses were conducted using the Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)databases,respectively,by processing data with the Metascape.Highly interconnected genes in the protein-protein interaction(PPI)network were analyzed using Cytoscape software.Bromodeoxyuridine,wound healing assay,collagen contraction assay and the expression of COL I andα-smooth muscle actin positive were applied to investigate the cell proliferation,migration and collagen synthesis.Quantitative real-time reverse transcription polymerase chain reaction was applied to determine the cell fibroblastic,tenogenic,and chondrogenic potential.RESULTS Bioinformatics analyses found two BMSC-derived exosomal miRNAs,has-miR-144-3p and hasmiR-23b-3p,were overlapped in three GSE datasets.PPI network analysis and functional enrichment analyses in the GO and KEGG databases indicated that both miRNAs regulated the PI3K/Akt signaling pathway by targeting phosphatase and tensin homolog(PTEN).In vitro experiments confirmed that miR-144-3p and miR-23b-3p stimulated proliferation,migration and collagen synthesis of NIH3T3 fibroblasts.Interfering with P

关键词： Exosome MicroRNA Fibroblast mesenchymal stem cell Tendon-bone healing