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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 *** 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’*** 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 *** system is achieved by bioorthogonally arming metabolic glycoengineered MSCs with microglial membrane-coated nanoparticles and an antioxidative extracellular protective *** 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 ***,the infarct’s inanimate milieu is transformed at the tissue level into a new living niche to facilitate *** 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 *** 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

Safety and efficiency of Wharton’s Jelly-derived mesenchymal stem cell administration in patients with traumatic brain injury:First results of a phase I study

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World Journal of stem cells 2024年第6期16卷 641-655页

作者： Serdar Kabatas ErdinçCivelek Osman Boyalı Gülseli Berivan Sezen Omer Ozdemir Yeliz Bahar-Ozdemir Necati Kaplan Eyüp Can Savrunlu Erdal Karaöz Department of Neurosurgery University of Health Sciences TurkeyGaziosmanpaşa Training and Research HospitalIstanbul 34360Türkiye Center for stem cell&Gene Therapy Research and Practice University of Health Sciences TurkeyIstanbul 34255Türkiye Department of Neurosurgery University of Health SciencesGaziosmanpaşa Training and Research HospitalIstanbul 34255Türkiye Department of Physical Medicine and Rehabilitation Health Sciences University Sultan Abdulhamid Han Training and Research HospitalIstanbul 34668Türkiye Department of Neurosurgery Istanbul Rumeli UniversityÇorlu Reyap HospitalTekirdağ59860Türkiye Department of Neurosurgery Nevşehir State HospitalNevşehir 50300Türkiye Center for Regenerative Medicine and stem cell Research&Manufacturing(LivMedcell) Liv HospitalIstanbul 34340Türkiye Department of Histology and Embryology Istinye UniversityFaculty of MedicineIstanbul 34010Türkiye Center for stem cell and Tissue Engineering Research and Practice Istinye UniversityIstanbul 34340Türkiye

BACKGROUND Traumatic brain injury(TBI)is characterized by a disruption in the normal function of the brain due to an injury following a trauma,which can potentially cause severe physical,cognitive,and emotional *** cell transplantation has evolved as a novel treatment modality in the management of TBI,as it has the potential to arrest the degeneration and promote regeneration of new cells in the ***’s Jelly-derived mesenchymal stem cells(WJ-MSCs)have recently shown beneficial effects in the functional recovery of neurological *** To evaluate the safety and efficiency of MSC therapy in *** We present 6 patients,4 male and 2 female aged between 21 and 27 years who suffered a *** 6 patients underwent 6 doses of intrathecal,intramuscular(i.m.)and intravenous transplantation of WJ-MSCs at a target dose of 1×106/kg for each application *** was assessed using the Modified Ashworth scale(MAS),motor function according to the Medical Research Council Muscle Strength Scale,quality of life was assessed by the Functional Independence Measure(FIM)scale and Karnofsky Performance Status *** Our patients showed only early,transient complications,such as subfebrile fever,mild headache,and muscle pain due to ***,which resolved within 24 *** the one year follow-up,no other safety issues or adverse events were *** 6 patients showed improvements in their cognitive abilities,muscle spasticity,muscle strength,performance scores and fine motor skills when compared before and after the *** values,which we used to assess spasticity,were observed to statistically significantly decrease for both left and right sides(P<0.001).The FIM scale includes both motor scores(P<0.05)and cognitive scores(P<0.001)and showed a significant increase in pretest posttest *** difference observed in the participants’Karnofsky Performance Scale values pre and post the intervention was statistically si

关键词： Traumatic brain injury Wharton Jelly stem cell therapy Transplantation mesenchymal stem cell

Searching for the optimal precondition procedure for mesenchymal stem/stromal cell treatment:Facts and perspectives

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World Journal of stem cells 2024年第6期16卷 615-618页

作者： Yu-Dong Zhao Yong-Can Huang Wei-Shi Li Department of Orthopedic Peking University Third HospitalBeijing 100191China Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies Orthopaedic Research CenterPeking University Shenzhen HospitalShenzhen 518036Guangdong ProvinceChina

mesenchymal stem/stromal cells are potential optimal cell sources for stem cell therapies,and pretreatment has proven to enhance cell vitality and *** a recent publication,Li et al explored a new combination of pretreatment ***,we present an editorial to comment on their work and provide our view on mesenchymal stem/stromal cell precondition.

关键词： mesenchymal stem cell Precondition Hypoxia Inflammation

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 *** acute CNS injury,brain microglia are among the first cells to respond and play a critical role in neural repair and ***,microglial activation can also impede CNS repair and amplify tissue damage,and phenotypic transformation may be responsible for this dual *** stem cell(MSC)-derived exosomes(Exos)are promising therapeutic agents for the treatment of acute CNS injuries due to their immunomodulatory and regenerative ***-Exos are nanoscale membrane vesicles that are actively released by cells and are used clinically as circulating biomarkers for disease diagnosis and ***-Exos can be neuroprotective in several acute CNS models,including for stroke and traumatic brain injury,showing great clinical *** 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 ***,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 *** the past few decades,mesenchymal stem cell(MSCs)studies have exponentially increased with a promising ***,regardless of the huge investment and the research attention given to stem cell research,FDA approval for clinical use is still *** 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 *** 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 *** 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 *** 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 ***,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 *** 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 *** 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 ***,it is demonstrated that the injection of this micelle with BMSCs retained disc height and alleviated IVDD in a rat needle puncture ***,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 ***,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 ***,there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse ***,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 ***,the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor(VDR)activation in *** 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 *** 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 ***,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 *** evidence has revealed that epigenetic regulation plays critical roles in the self-renew,lineage-commitment,survival,and function of stem ***,epigenetic alterations are considered important drivers of stem cell dysfunction during *** 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 *** 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 ***,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