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Pathological and therapeutic effects of extracellular vesicles in neurological and neurodegenerative diseases

Neural regeneration Research 2024年第1期19卷 55-61页

作者： Paula lzquierdo-Altarejos Victoria Moreno-Manzano Vicente Felipo laboratory of Neurobiology Centro Investigación Príncipe FelipeValenciaSpain neuronal and tissue regeneration laboratory Centro Investigación Príncipe FelipeValenciaSpain

Extracellular vesicles are released by all cell types and contain proteins,microRNAs,mRNAs,and other bioactive *** vesicles play an important role in intercellular communication and in the modulation of the immune system and *** cargo of extra cellular vesicles(e.g.,proteins and microRNAs)is altered in pathological *** vesicles contribute to the pathogenesis of many pathologies associated with sustained inflammation and neuroinflammation,including cance r,diabetes,hype rammonemia and hepatic encephalopathy,and other neurological and neurodegenerative *** vesicles may cross the blood-brain barrier and transfer pathological signals from the periphery to the *** contributes to inducing neuroinflammation and cognitive and motor impairment in hyperammonemia and hepatic encephalopathy and in neurodegenerative *** mechanisms involved are beginning to be unde *** example,increased tumor necrosis factor a in extracellular vesicles from plasma of hype rammonemic rats induces neuroinflammation and motor impairment when injected into normal *** the mechanisms by which extracellular vesicles contribute to the pathogenesis of these diseases will help to develop new treatments and diagnostic tools for their easy and early *** contrast,extra cellular vesicles from mesenchymal stem cells have therapeutic utility in many of the above pathologies,by reducing inflammation and neuroinflammation and improving cognitive and motor *** extra cellular vesicles recapitulate the beneficial effects of mesenchymal stem cells and have advantages as therapeutic tools:they are less immunoge nic,may not diffe rentiate to malignant cells,cross the blood-brain barrier,and may reach more easily target *** vesicles from mesenchymal stem cells have beneficial effects in models of ischemic brain injury,Alzheimer's and Parkinson's diseases,hyperammonemia,and

关键词： extracellular vesicles inflammation cognitive function mesenchymal stem cells neurodegenerative diseases neuroinflammation therapy transforming growth factor-β

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The emerging role of mesenchymal stem cell-derived extracellular vesicles to ameliorate hippocampal NLRP3 inflammation induced by binge-like ethanol treatment in adolescence

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Neural regeneration Research 2025年第4期20卷 1153-1163页

作者： Susana Mellado María JoséMorillo-Bargues Carla Perpiñá-Clérigues Francisco García-García Victoria Moreno-Manzano Consuelo Guerri María Pascual Department of Physiology School of Medicine and DentistryUniversity of ValenciaValenciaSpain Bioinformatics and Biostatistics Unit Príncipe Felipe Research CenterValenciaSpain neuronal and tissue regeneration laboratory Príncipe Felipe Research CenterValenciaSpain

Our previous studies have reported that activation of the NLRP3(NOD-,LRR-and pyrin domain-containing protein 3)-inflammasome complex in ethanol-treated astrocytes and chronic alcohol-fed mice could be associated with neuroinflammation and brain *** stem cell-derived extracellular vesicles(MSC-EVs)have been shown to restore the neuroinflammatory response,along with myelin and synaptic structural alterations in the prefrontal cortex,and alleviate cognitive and memory dysfunctions induced by binge-like ethanol treatment in adolescent *** the therapeutic role of the molecules contained in mesenchymal stem cell-derived extracellular vesicles,the present study analyzed whether the administration of mesenchymal stem cell-derived extracellular vesicles isolated from adipose tissue,which inhibited the activation of the NLRP3 inflammasome,was capable of reducing hippocampal neuroinflammation in adolescent mice treated with binge *** demonstrated that the administration of mesenchymal stem cell-derived extracellular vesicles ameliorated the activation of the hippocampal NLRP3 inflammasome complex and other NLRs inflammasomes(e.g.,pyrin domain-containing 1,caspase recruitment domain-containing 4,and absent in melanoma 2,as well as the alterations in inflammatory genes(interleukin-1β,interleukin-18,inducible nitric oxide synthase,nuclear factor-kappa B,monocyte chemoattractant protein-1,and C–X3–C motif chemokine ligand 1)and miRNAs(miR-21a-5p,miR-146a-5p,and miR-141-5p)induced by binge-like ethanol treatment in adolescent *** analysis further revealed the involvement of miR-21a-5p and miR-146a-5p with inflammatory target genes and NOD-like receptor signaling *** together,these findings provide novel evidence of the therapeutic potential of MSC-derived EVs to ameliorate the hippocampal neuroinflammatory response associated with NLRP3 inflammasome activation induced by binge drinking in adolescence.

关键词： adolescence binge-like ethanol treatment extracellular vesicles hippocampus mesenchymal stem cells neuroinflammation NOD-,LRR-and pyrin domain-containing protein 3(NLRP3)

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Nanocarrier-mediated siRNA delivery:a new approach for the treatment of traumatic brain injury-related Alzheimer's disease

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Neural regeneration Research 2025年第9期20卷 2538-2555页

作者： Jie Jin Huajing Zhang Qianying Lu Linqiang Tian Sanqiao Yao Feng Lai Yangfan Liang Chuanchuan Liu Yujia Lu Sijia Tian Yanmei Zhao Wenjie Ren Institute of Disaster and Emergency Medicine Tianjin UniversityTianjinChina Key laboratory for Disaster Medicine Technology TianjinChina Henan Medical Key laboratory for Research of Trauma and Orthopedics The Third Affiliated Hospital of Xinxiang Medical UniversityXinxiangHenan ProvinceChina Clinical Medical Center of tissue Engineering and regeneration Xinxiang Medical UniversityXinxiangHenan ProvinceChina Institutes of Health Central Plain Xinxiang Medical UniversityXinxiangHenan ProvinceChina School of Public Health Xinxiang Medical UniversityXinxiangHenan ProvinceChina

Traumatic brain injury and Alzheimer's disease share pathological similarities,including neuronal loss,amyloid-βdeposition,tau hyperphosphorylation,blood-brain barrier dysfunction,neuroinflammation,and cognitive ***,traumatic brain injury can exacerbate Alzheimer's disease-like pathologies,potentially leading to the development of Alzheimer's *** offer a potential solution by facilitating the delive ry of small interfering RNAs across the blood-brain barrier for the targeted silencing of key pathological genes implicated in traumatic brain injury and Alzheimer's disease.U nlike traditional approaches to neuro regeneration,this is a molecula r-targeted strategy,thus avoiding non-specific drug *** review focuses on the use of nanocarrier systems for the efficient and precise delive ry of siRNAs,discussing the advantages,challenges,and future *** principle,siRNAs have the potential to target all genes and non-targetable protein s,holding significant promise for treating various *** the various therapeutic approaches currently available for neurological diseases,siRNA gene silencing can precisely"turn off"the expression of any gene at the genetic level,thus radically inhibiting disease progression;however,a significant challenge lies in delivering siRNAs across the blood-brain *** have received increasing attention as an innovative drug delive ry tool fo r the treatment of brain *** are considered a potential therapeutic strategy with the advantages of being able to cross the blood-brain barrier,targeted drug delivery,enhanced drug stability,and multifunctional *** use of nanoparticles to deliver specific modified siRNAs to the injured brain is gradually being recognized as a feasible and effective *** this strategy is still in the preclinical exploration stage,it is expected to achieve clinical translation in the future,creating a new field of molecular tar

关键词： blood-brain barrier cognitive dysfunction exosomes gene silencing immunotherapy inorganic nanomaterials liposome nanoparticles neuroinflammation polymer nanoparticles stem cells

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Regenerative treatment of ophthalmic diseases with stem cells:Principles,progress,and challenges

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Advances in Ophthalmology Practice and Research 2024年第2期4卷 52-64页

作者： Yifei Niu Junfeng Ji Ke Yao Qiuli Fu Eye Center of the Second Affiliated Hospital Zhejiang University School of MedicineHangzhouZhejiang ProvinceChina Zhejiang Provincial Key lab of Ophthalmology HangzhouZhejiang ProvinceChina Center of Stem Cell and Regenerative Medicine School of MedicineZhejiang UniversityHangzhouZhejiang ProvinceChina Zhejiang Provincial Key laboratory of tissue Engineering and Regenerative Medicine HangzhouChina

Background:Degenerate eye disorders,such as glaucoma,cataracts and age-related macular degeneration(AMD),are prevalent causes of blindness and visual impairment *** eye disorders,including limbal stem cell deficiency(LSCD),dry eye diseases(DED),and retinitis pigmentosa(RP),result in symptoms such as ocular discomfort and impaired visual function,significantly impacting quality of *** therapies are limited,primarily focus on delaying disease progression,while emerging stem cell therapy directly targets ocular tissues,aiming to restore ocular function by reconstructing ocular *** text:The utilization of stem cells for the treatment of diverse degenerative ocular diseases is becoming increasingly significant,owing to the regenerative and malleable properties of stem cells and their functional ***,stem cell therapy for ophthalmopathy involves various cell types,such as embryonic stem cells(ESCs),induced pluripotent stem cells(iPSCs),mesenchymal stem cells(MSCs),and retinal progenitor cells(RPCs).In the current article,we will review the current progress regarding the utilization of stem cells for the regeneration of ocular tissue covering key eye tissues from the cornea to the *** therapies aim to address the loss of functional cells,restore damaged ocular tissue and or in a paracrine-mediated *** also provide an overview of the ocular disorders that stem cell therapy is targeting,as well as the difficulties and opportunities in this ***:Stem cells can not only promote tissue regeneration but also release exosomes to mitigate inflam-mation and provide neuroprotection,making stem cell therapy emerge as a promising approach for treating a wide range of eye disorders through multiple mechanisms.

关键词： Stem cell Ocular diseases Induced pluripotent stem cells Mesenchymal stem cells Cataracts Glaucoma Diabetic retinopathy Retinal degenerative diseases

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Biofabrication of nanocomposite-based scaffolds containing human bone extracellularmatrix for the differentiation of skeletal stem and progenitor cells

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Bio-Design and Manufacturing 2024年第2期7卷 121-136页

作者： Yang-Hee Kim Janos M.Kanczler Stuart Lanham Andrew Rawlings Marta Roldo Gianluca Tozzi Jonathan I.Dawson Gianluca Cidonio Richard O.C.Oreffo Faculty of Medicine Bone and Joint Research GroupCentre for Human DevelopmentStem Cells and RegenerationInstitute of Developmental SciencesUniversity of SouthamptonSouthampton SO166YDUK School of Pharmacy and Biomedical Science University of PortsmouthPortsmouth PO12DTUK School of Engineering Faculty of Engineering and ScienceUniversity of GreenwichGreenwich ME44TBUK Center for Life Nano-and Neuro-Science(CLN2S) Italian Institute of Technology00161 RomeItaly

Autograft or metal implants are routinely used in skeletal ***,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering *** use of native human bone tissue for synthesizing a biomimeticmaterial inkfor three-dimensional(3D)bioprintingof skeletal tissueis anattractivestrategyfor ***,human bone extracellular matrix(bone-ECM)offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells(HBMSCs)to proliferate and differentiate along the osteogenic *** this study,we engineered a novel material ink(lab)by blending human bone-ECM(B)with nanoclay(L,Laponite®)and alginate(A)polymers using extrusion-based *** inclusion of the nanoﬁller and polymeric material increased the rheology,printability,and drug retention properties and,critically,the preservation of HBMSCs viability upon *** composite of human bone-ECM-based 3D constructs containing vascular endothelial growth factor(VEGF)enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane(CAM)*** inclusion of bone morphogenetic protein-2(BMP-2)with the HBMSCs further enhanced vascularization and mineralization after only seven *** study demonstrates the synergistic combination of nanoclay with biomimetic materials(alginate and bone-ECM)to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair.

关键词： Extracellular matrix Nanoclay Bone 3D bioprinting

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Chemokine platelet factor 4 accelerates peripheral nerve regeneration by regulating Schwann cell activation and axon elongation

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Neural regeneration Research 2024年第1期19卷 190-195页

作者： Miao Gu Xiao Cheng Di Zhang Weiyan Wu Yi Cao Jianghong He Key laboratory of Neuroregeneration of Jiangsu and Ministry of Education Co-innovation Center of NeuroregenerationNMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology ProductsNantong UniversityNantongJiangsu ProvinceChina School of Basic Medical Sciences Hebei Key Laboratory of Nerve Injury and RepairChengde Medical UniversityChengdeHebei ProvinceChina

Schwann cells in peripheral nerves react to traumatic nerve injury by attempting to grow and *** r,it is unclear what factors play a role in this *** this study,we searched a GEO database and found that expression of platelet factor 4 was markedly up-regulated after sciatic nerve *** factor is an important molecule in cell apoptosis,diffe rentiation,survival,and ***,polymerase chain reaction and immunohistochemical staining confirmed the change in platelet factor 4 in the sciatic nerve at different time points after ***-linked immunosorbent assay confirmed that platelet factor 4 was secreted by Schwann *** also found that silencing platelet factor 4 decreased the proliferation and migration of primary cultured Schwann cells,while exogenously applied platelet factor 4 stimulated Schwann cell prolife ration and migration and neuronal axon ***,knocking out platelet factor 4 inhibited the prolife ration of Schwann cells in injured rat sciatic *** findings suggest that Schwann cell-secreted platelet factor 4 may facilitate peripheral nerve repair and regeneration by regulating Schwann cell activation and axon ***,platelet factor 4 may be a potential therapeutic target for traumatic peripheral nerve injury.

关键词： axon elongation bioinformatic analysis cell migration cell proliferation dorsal root ganglia peripheral nerve regeneration peripheral nerve trauma platelet factor 4 rat sciatic nerve Schwann cells

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Efficient and rapid conversion of human astrocytes and ALS mouse model spinal cord astrocytes into motor neuron-like cells by defined small molecules

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Military Medical Research 2021年第1期8卷 62-78页

作者： An-Dong Zhao Hua Qin Meng-Li Sun Kui Ma Xiao-Bing Fu Tianjin Medical University Tianjin 300070China Research Center for tissue Repair and regeneration Affiliated to the Medical Innovation Research Division and 4th Medical Center PLA General Hospital and PLA Medical College28 Fu Xing RoadHaidian DistrictBeijing 100853China PLA Key laboratory of tissue Repair and Regenerative Medicine and Beijing Key Research laboratory of Skin Injury Repair and RegenerationBeijing 100048China Research Unit of Trauma Care Tissue Repair and RegenerationChinese Academy of Medical SciencesBeijing 100048China

Background: Motor neuron degeneration or loss in the spinal cord is the characteristic phenotype of motor neuron diseases or spinal cord injuries. Being proliferative and located near neurons, astrocytes are considered ideal cell sources for regenerating ***: We selected and tested different combinations of the small molecules for inducing the conversion of human and mouse astrocytes into neurons. Microscopic imaging and immunocytochemistry analyses were used to characterize the morphology and phenotype of the induced neurons while RT-q PCR was utilized to analyze changes in gene expression. In addition, whole-cell patch-clamp recordings were measured to examine the electrophysiological properties of induced ***: The results showed that human astrocytes could be rapidly and efficiently converted into motor neuronlike cells by treatment with defined small molecules, with a yield of over 85% motor neuron-like cells attained. The induced motor neuron-like cells expressed the pan-neuronal markers TUJ1, MAP2, Neu N, and Synapsin 1 and motor neuron markers HB9, ISL1, CHAT, and VACh T. During the conversion process, the cells did not pass through a proliferative neural progenitor cell intermediate. The induced motor neurons were functional, showing the electrophysiological properties of neurons. The same chemical cocktail could induce spinal cord astrocytes from an amyotrophic lateral sclerosis mouse model carrying a SOD1 mutation to become motor neuron-like cells that exhibited a decrease in cell survival and an increase in oxidative stress compared to that observed in wild-type MNs derived from healthy mice. Moreover, the chemical induction reduced oxidative stress in the mutant ***: The results of the present study demonstrated the feasibility of chemically converting human and mouse astrocytes into motor neuron-like cells that are useful for neurodegenerative disease modeling and regenerative medicine.

关键词： Human astrocyte Motor neuron Reprogramming Transdifferentiation Conversion regeneration Amyotrophic lateral sclerosis Neurodegenerative

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Direct conversion of human fibroblasts into dopaminergic neuron-like cells using small molecules and protein factors

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Military Medical Research 2021年第2期8卷 162-173页

作者： Hua Qin An-Dong Zhao Meng-Li Sun Kui Ma Xiao-Bing Fu Research Center for tissue Repair and regeneration affiliated to the Medical Innovation Research Division and 4th Medical Center PLA General Hospital and PLA Medical College28 Fu Xing RoadHaidian DistrictBeijing 100853China Tianjin Medical University Tianjin 300070China PLA Key laboratory of tissue Repair and Regenerative Medicine and Beijing Key Research laboratory of Skin Injury Repair and RegenerationBeijing 100048China Research Unit of Trauma Care Tissue Repair and RegenerationChinese Academy of Medical Sciences2019RU051Beijing 100048China

Background:Generation of neurons is essential in cell replacement therapy for neurodegenerative disorders like Parkinson’s *** studies have reported the generation of dopaminergic(DA)neurons from mouse and human fibroblasts by ectopic expression of transcription factors,in which genetic manipulation is associated with potential ***:The small molecules and protein factors were selected based on their function to directly induce human fetal lung IMR-90 fibroblasts into DA neuron-like ***,immunocytochemical,and RT-qPCR analyses were used to characterize the morphology,phenotype,and gene expression features of the induced *** wholecell patch-clamp recordings were exploited to measure the electrophysiological ***:Human IMR-90 fibroblasts were rapidly converted into DA neuron-like cells after the chemical induction using small molecules and protein factors,with a yield of approximately 95%positive TUJ1-positive *** induced DA neuron-like cells were immunopositive for pan-neuronal markers MAP2,NEUN,and Synapsin 1 and DA markers TH,DDC,DAT,and *** chemical induction process did not involve a neural progenitor/stem cell intermediate *** induced neurons could fire single action potentials,which reflected partially the electrophysiological properties of ***:We developed a chemical cocktail of small molecules and protein factors to convert human fibroblasts into DA neuron-like cells without passing through a neural progenitor/stem cell intermediate *** induced DA neuron-like cells from human fibroblasts might provide a cellular source for cell-based therapy of Parkinson’s disease in the future.

关键词： Human fibroblasts Dopaminergic neurons Parkinson's disease Small molecules Reprogramming Transdifferentiation

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BMPRⅡ^(+)neural precursor cells isolated and characterized from organotypic neurospheres:an in vitro model of human fetal spinal cord development

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Neural regeneration Research 2024年第2期19卷 447-457页

作者： Michael W.Weible II Michael D.Lovelace Hamish D.Mundell Tsz Wai Rosita Pang Tailoi Chan-Ling Bosch Institute Discipline of Anatomy and Histology(F13)University of SydneySydneyNSWAustralia School of Environment and Science Griffith UniversityNathanQLDAustralia Discipline of Medicine Nepean Clinical SchoolFaculty of Medicine and HealthUniversity of SydneyKingswoodNSWAustralia New South Wales Brain tissue Resource Centre School of Medical SciencesFaculty of Medicine and HealthUniversity of SydneyCharles Perkins Centre(D17)SydneyNSWAustralia

Roof plate secretion of bone morphogenetic proteins(BMPs)directs the cellular fate of sensory neurons during spinal cord development,including the formation of the ascending sensory columns,though their biology is not well ***-ⅡBMP receptor(BMPRⅡ),the cognate receptor,is expressed by neural precursor cells during embryogenesis;however,an in vitro method of enriching BMPRⅡ^(+)human neural precursor cells(hNPCs)from the fetal spinal cord is *** was undertaken on intact second-trimester human fetal spinal cord using antibodies to BMPRⅡand leukemia inhibitory factor(LIF).Regions of highest BMPRⅡ^(+)immunofluorescence localized to sensory *** and meningeal-associated BMPRⅡ^(+)vascular cells were identified in both intact fetal spinal cord and cortex by co-positivity with vascular lineage markers,CD34/*** immunostaining identified a population of somas concentrated in dorsal and ventral horn interneurons,mirroring the expression of LIF receptor/CD118.A combination of LIF supplementation and high-density culture maintained culture growth beyond 10 passages,while synergistically increasing the proportion of neurospheres with a stratified,*** neurospheres were characterized by BMPRⅡ^(+)/MAP2ab^(+/–)/βⅢ-tubulin^(+)/nestin^(–)/vimentin^(–)/GFAP^(–)/NeuN^(–)surface hNPCs surrounding a heterogeneous core ofβⅢ-tubulin^(+)/nestin^(+)/vimentin^(+)/GFAP^(+)/MAP2ab^(–)/NeuN^(–)multipotent *** cultures from tripotential neurospheres contained neuronal(βⅢ-tubulin^(+)),astrocytic(GFAP+),and oligodendrocytic(O4+)lineage ***-activated cell sorting-sorted BMPRⅡ^(+)hNPCs were MAP2ab^(+/–)/βⅢ-tubulin^(+)/GFAP^(–)/O4^(–)in *** is the first isolation of BMPRⅡ^(+)hNPCs identified and characterized in human fetal spinal *** data show that LIF combines synergistically with high-density reaggregate cultures to support the organotypic reorganization of neurospheres,characterize

关键词： BMPRⅡ bone morphogenetic protein histotypic human spinal cord development leukemia inhibitory factor neurosphere organotypic reaggregate sensory columns

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Reorganization of spinal neural circuitry and functional recovery after spinal cord injury

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Neural regeneration Research 2015年第2期10卷 201-202页

作者： Raffaele Nardone Eugen Trinka Department of Neurology Christian Doppler Klinik Paracelsus Medical University Spinal Cord Injury and tissue regeneration Center Paracelsus Medical University Department of Neurology Franz Tappeiner Hospital

The ability of the adult central nervous system to reorganize its circuits over time is the key to understand the functional improvement in subjects with spinal cord injury （SCI）. Adaptive changes within spared neuronal circuits may occur at cortical, brainstem, or spinal cord level, both above and below a spinal lesion （Bareyre et al., 2004）. At each level the reorganization is a very dynamic process, and its degree is highly variable, depending on several factors, including the age of the subject when SCI has occurred and the rehabilitative therapy. The use of electrophysiological techniques to assess these functional changes in neural networks is of great interest, because invasive methodologies as employed in preclinical models can obviously not be used in clinical studies.

关键词： SCI Reorganization of spinal neural circuitry and functional recovery after spinal cord injury TSR

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