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The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke

Neural Regeneration Research 2024年第9期19卷 1998-2003页

作者： Yiqing Wang Chuheng Chang Renzhi Wang Xiaoguang Li Xinjie Bao 4+4 Doctor Medical Program Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijingChina Department of Neurosurgery Peking Union Medical College HospitalPeking Union Medical CollegeChinese Academy of Medical SciencesBeijingChina Beijing Key Laboratory for Biomaterials and Neural Regeneration School of Biological Science and Medical EngineeringBeihang UniversityBeijingChina Department of Neurobiology School of Basic Medical SciencesCapital Medical UniversityBeijingChina

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

关键词： ischemic stroke mesenchymal stem cells metabolomics multilevel omics neural stem/progenitor cells neuroinflammation pathophysiology proteomics stem cell therapy transcriptomes

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Proteomic profiling of cerebrospinal fluid in pediatric myelin oligodendrocyte glycoprotein antibody-associated disease

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World Journal of Pediatrics 2024年第3期20卷 259-271页

作者： Yi-Long Wang Meng-Ying Zhu Zhe-Feng Yuan Xiao-Yan Ren Xiao-Tong Guo Yi Hua Lu Xu Cong-Ying Zhao Li-Hua Jiang Xin Zhang Guo-Xia Sheng Pei-Fang Jiang Zheng-Yan Zhao Feng Gao Department of Neurology Children's HospitalZhejiang University School of MedicineHangzhou 310052China Children's Hospital Zhejiang University School of MedicineHangzhou 310052China Children's Hospital National Clinical Research Center for Child HealthZhejiang University School of MedicineHangzhou 310052China

Background Myelin oligodendrocyte glycoprotein(MOG)antibody-associated disease(MOGAD)is an autoimmune demy-elinating disorder of the central nervous system.Methods Extracted proteins from 34 cerebrospinal fluid(CSF)samples[patients with MOGAD(MOG group,n=12);healthy controls(HC group,n=12);patients with MOG seronegative and metagenomics next-generation sequencing-negative inflammatory neurological diseases(IND group,n=10)]were processed and subjected to label-free quantitative proteomics.Supervised partial least squares-discriminant analysis(PLS-DA)and orthogonal PLS-DA(O-PLS-DA)models were also performed based on proteomics data.Functional analysis of differentially expressed proteins(DEPs)was performed using Gene Ontology,InterPro,and Kyoto Encyclopedia Genes and Genomes.An enzyme-linked immunosorbent assay was used to determine the complement levels in serum from patients with MOGAD.Results Four hundred and twenty-nine DEPs(149 upregulated and 280 downregulated proteins)were identified in the MOG group compared to the HC group according to the P value and fold change(FC).Using the O-PLS-DA model,872 differentially abundant proteins were identified with variable importance projection(VIP)scores>1.Five proteins(gamma-glutamyl hydrolase,cathepsin F,interalpha-trypsin inhibitor heavy chain 5,latent transforming growth factor beta-binding protein 4 and leukocyte-associated immunoglobulin-like receptor 1)overlapping between the top 30 DEPs with top-ranked P value and FC and top 30 proteins in PLS-DA VIP lists were acquired.Functional analysis revealed that the dysregulated proteins in the MOG group were primarily involved in complement and coagulation cascades,cell adhesion,axon guidance,and glycosphingolipid biosynthesis compared to the HC group.Conclusion The proteomic alterations in CSF samples from children with MOGAD identified in the current study might provide opportunities for developing novel biomarker candidates.

关键词： Acute disseminated encephalomyelitis Cerebrospinal fluid Complement cascades Myelin oligodendrocyte glycoprotein-associated disease proteomics

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Cerebral furin deficiency causes hydrocephalus in mice

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Genes & Diseases 2024年第3期11卷 438-451页

作者： Shiqi Xie Xiaoyong Xie Jing Tang Biao Luo Jian Chen Qixin Wen Jianrong Zhou Guojun Chen Nursing College Chongqing Medical UniversityChongqing 400016China Department of Neurology The First Affiliated Hospital of Chongqing Medical UniversityChongqing Key Laboratory of Major Neurological and Mental DisordersChongqing Key Laboratory of NeurologyChongqing 400016China

Furin is a pro-protein convertase that moves between the trans-Golgi network and cell surface in the secretory pathway.We have previously reported that cerebral overexpres-sion of furin promotes cognitive functions in mice.Here,by generating the brain-specific furin conditional knockout(ckO)mice,we investigated the role of furin in brain development.We found that furin deficiency caused early death and growth retardation.Magnetic resonance im-aging showed severe hydrocephalus.In the brain of furin cko mice,impaired ciliogenesis and the derangement of microtubule structures appeared along with the down-regulated expres-sion of RAB28,a ciliary vesicle protein.In line with the widespread neuronal loss,ependymal cell layers were damaged.Further proteomics analysis revealed that cell adhesion molecules including astrocyte-enriched ITGB8 and BCAR1 were altered in furin cKO mice;and astrocyte overgrowth was accompanied by the reduced expression of sox9,indicating a disrupted differ-entiation into ependymal cells.Together,whereas alteration of RAB28 expression correlated with the role of vesicle trafficking in ciliogenesis,dysfunctional astrocytes might be involved in ependymal damage contributing to hydrocephalus in furin ckO mice.The structural and mo-lecular alterations provided a clue for further studying the potential mechanisms of furin.

关键词： Astrocyte Ciliogenesis Conditionalknockout Ependymal Furin Hydrocephalus proteomics

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Patient-derived induced pluripotent stem cells with a MERTK mutation exhibit cell junction abnormalities and aberrant cellular differentiation potential

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World Journal of Stem Cells 2024年第5期16卷 512-524页

作者： Hang Zhang Ling-Zi Wu Zhen-Yu Liu Zi-Bing Jin Beijing Institute of Ophthalmology Beijing Tongren Eye CenterBeijing Tongren HospitalCapital Medical UniversityBeijing 100730China

BACKGROUND Human induced pluripotent stem cell(hiPSC)technology is a valuable tool for generating patient-specific stem cells,facilitating disease modeling,and invest-igating disease mechanisms.However,iPSCs carrying specific mutations may limit their clinical applications due to certain inherent characteristics.AIM To investigate the impact of MERTK mutations on hiPSCs and determine whether hiPSC-derived extracellular vesicles(EVs)influence anomalous cell junction and differentiation potential.METHODS We employed a non-integrating reprogramming technique to generate peripheral blood-derived hiPSCs with and hiPSCs without a MERTK mutation.Chromo-somal karyotype analysis,flow cytometry,and immunofluorescent staining were utilized for hiPSC identification.Transcriptomics and proteomics were employed to elucidate the expression patterns associated with cell junction abnormalities and cellular differentiation potential.Additionally,EVs were isolated from the supernatant,and their RNA and protein cargos were examined to investigate the involvement of hiPSC-derived EVs in stem cell junction and differentiation.RESULTS The generated hiPSCs,both with and without a MERTK mutation,exhibited normal karyotype and expressed pluripotency markers;however,hiPSCs with a MERTK mutation demonstrated anomalous adhesion capability and differentiation potential,as confirmed by transcriptomic and proteomic profiling.Furthermore,hiPSC-derived EVs were involved in various biological processes,including cell junction and differentiation.CONCLUSION HiPSCs with a MERTK mutation displayed altered junction characteristics and aberrant differentiation potential.Furthermore,hiPSC-derived EVs played a regulatory role in various biological processes,including cell junction and differentiation.

关键词： Cell junction Cellular differentiation Extracellular vesicle Human induced pluripotent stem cells Transcriptomics proteomics

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Latest insights into the global epidemiological features,screening,early diagnosis and prognosis prediction of esophageal squamous cell carcinoma

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World Journal of Gastroenterology 2024年第20期30卷 2638-2656页

作者： Yi-Xin Zhao He-Ping Zhao Meng-Yao Zhao Yan Yu Xi Qi Ji-Han Wang Jing Lv Department of Clinical Laboratory Honghui HospitalXi’an Jiaotong UniversityXi’an 710054Shaanxi ProvinceChina Institute of Medical Research Northwestern Polytechnical UniversityXi’an 710072Shaanxi ProvinceChina

As a highly invasive carcinoma,esophageal cancer(EC)was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020.Esophageal squamous cell carcinoma(ESCC)is the major histological subtype of EC,and its incidence and mortality rates are decreasing globally.Due to the lack of specific early symptoms,ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis,and the incidence and mortality rates are still high in many countries,especially in China.Therefore,enormous challenges still exist in the management of ESCC,and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC.Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated,certain promising biomarkers are being investigated to facilitate clinical decision-making.With the advent and advancement of highthroughput technologies,such as genomics,proteomics and metabolomics,valuable biomarkers with high sensitivity,specificity and stability could be identified for ESCC.Herein,we aimed to determine the epidemiological features of ESCC in different regions of the world,especially in China,and focused on novel molecular biomarkers associated with ESCC screening,early diagnosis and prognosis prediction.

关键词： Esophageal squamous cell carcinoma Epidemiology Diagnosis Genomics proteomics Metabolomics

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Neuroprotective effects of acteoside in a glaucoma mouse model by targeting Serta domain-containing protein 4

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International Journal of Ophthalmology(English edition) 2024年第4期17卷 625-637页

作者： Hui-Jie Hao Ya-Hong Li Bo Yu Xun Liu Yan Zhang Xiao-Li Xing Tianjin Key Laboratory of Retinal Functions and Diseases Tianjin Branch of National Clinical Research Center for Ocular DiseaseEye Institute and School of OptometryTianjin Medical University Eye HospitalTianjin 300384China

AIM:To explore the therapeutic effect and main molecular mechanisms of acteoside in a glaucoma model in DBA/2J mice.METHODS:proteomics was used to compare the differentially expressed proteins of C57 and DBA/2J mice.After acteoside administration in DBA/2J mice,anterior segment observation,intraocular pressure(IOP)monitoring,electrophysiology examination,and hematoxylin and eosin staining were used to analyze any potential effects.Immunohistochemistry(IHC)assays were used to verify the proteomics results.Furthermore,retinal ganglion cell 5(RGC5)cell proliferation was assessed with cell counting kit-8(CCK-8)assays.Serta domain-containing protein 4(Sertad4)mRNA and protein expression levels were measured by qRT-PCR and Western blot analysis,respectively.RESULTS:proteomics analysis suggested that Sertad4 was the most significantly differentially expressed protein.Compared with the saline group,the acteoside treatment group showed decreased IOP,improved N1-P1 wave amplitudes,thicker retina,and larger numbers of cells in the ganglion cell layer(GCL).The IHC results showed that Sertad4 expression levels in DBA/2J mice treated with acteoside were significantly lower than in the saline group.Acteoside treatment could improve RGC5 cell survival and reduce the Sertad4 mRNA and protein expression levels after glutamate injury.CONCLUSION:Sertad4 is differentially expressed in DBA/2J mice.Acteoside can protect RGCs from damage,possibly through the downregulation of Sertad4,and has a potential use in glaucoma treatment.

关键词： glaucoma acteoside Serta domaincontaining protein 4 proteomics mice

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Combined proteomic and metabolomic studies on the liver of Amur sturgeon Acipenser schrenckii under titanium dioxide nanoparticle exposure

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Journal of Oceanology and Limnology 2024年第3期42卷 1001-1015页

作者： Zhou ZHOU Ting LIU Jie KONG Zhenxing ZHAO Junquan ZHU Key Laboratory of Aquacultural Biotechnology Ministry of Educationand Key Laboratory of Marine Biotechnology of Zhejiang ProvinceCollege of Marine SciencesNingbo UniversityNingbo 315000China Guizhou Fisheries Research Institute Guizhou Academy of Agriculture SciencesGuiyang 550000China

Nanomaterials,particularly titanium dioxide nanoparticles(TiO_(2)-NPs),are extensively utilized across various industries.However,their environmental release has raised concerns regarding their potential ecological and environmental impacts.The reproductive toxicity of TiO_(2)-NPs in fish species has attracted considerable attention,yet conflicting research outcomes have been reported.We investigated the effects of TiO_(2)-NPs exposure on the liver of juvenile Amur sturgeon Acipenser schrenckii using label-free proteomic and untargeted metabolomic analyses.The experiment included a control group and three groups exposed to different concentrations of TiO_(2)-NPs(low,TL;medium,TM;high,TH).Compared to the control group,9,19,and 25 proteins and 35,73,and 158 metabolites were differentially expressed in the TH,TM,and TL TiO_(2)-NP-exposed groups,respectively.The differentially expressed genes(DEGs)were enriched in the Kyoto Encyclopedia for Genes and Genomes(KEGG)pathways related to glycolysis and gluconeogenesis.Moreover,among the 126 correlated proteins,the most enriched pathways were associated with endocytosis and protein processing in the endoplasmic reticulum.Notably,syringic acid was significantly downregulated across all three TiO_(2)-NP-exposed groups.To obtain a comprehensive overview of the TiO_(2)-NP-induced expression changes,a co-regulated network of proteins and metabolites associated with TiO_(2)-NPs exposure was constructed.Exposure to TiO_(2)-NPs led to enrichment and alteration of pathways related to immune responses,including endocytosis,protein processing in the endoplasmic reticulum,and peroxisome proliferator-activated receptor(PPAR)signaling.In conclusion,our findings indicate that exposure to TiO_(2)-NPs might disrupt glucose metabolism and induce immune responses,thus contributing to our understanding of the environmental impacts of nanomaterials and highlighting the need for further research and development of potential mitigation strategies.

关键词： TiO_(2)-nanoparticle exposure proteomics metabolomics glucose metabolism immune response

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Changes in milk fat globule membrane proteins along lactation stage of Laoshan dairy goat

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Journal of Integrative Agriculture 2024年第5期23卷 1737-1748页

作者： Chuozi Liang Zhongna Yu Guangming Zhu Yixuan Li Xueheng Sun Hongning Jiang Qijing Du Rongbo Fan Jun Wang Yongxin Yang Rongwei Han College of Food Science and Engineering Qingdao Agricultural UniversityQingdao 266109China Bathurst Future Agri-Tech Institute Qingdao Agricultural UniversityQingdao 266109China Haidu Cllege Qingdao Agricultural UniversityQingdao 266109China

The milk fat globule membrane(MFGM)is a complex structure with numerous functions,and its composition is affected by many factors.There have been few systematic investigations on goat MFGM proteome profiling during lactation.Individual milk samples from 15 healthy dairy goats were obtained at six lactation time points for investigation of the MFGM proteome using both data-independent acquisition(DIA)and data-dependent acquisition(DDA)proteomics techniques combined with multivariate statistical analysis.Using the DIA method,890 variably abundant MFGM proteins were discovered throughout the lactation cycle.From 1 to 240 d,butyrophilin subfamily 1 member A1,lipoprotein lipase,perilipin-2,and adipose triglyceride lipase were upregulated,while APOE,complement C3,clusterin,and IgG were downregulated.Furthermore,from 1 to 90 d,annexin A1,annexin A2,and antithrombin-ll were downregulated,then upregulated by d 240.Albumin had a high degree of connectedness,indicating that it was a key protein,according to protein-protein interaction research.Overall,our findings gave new insights into the biological features of MFGM protein in goat milk throughout lactation,which may aid in the creation of specialized MFGM products and infant formula.

关键词： goat milk fat globule membrane protein data-independent acquisition(DIA) data-dependent acquisition(DDA) lactation proteomics

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Stigma-Specific Comparative Proteomic Analysis Reveals the Distyly Response to Self-Incompatibility in Plumbago auriculata Lam

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Phyton-International Journal of Experimental Botany 2024年第4期93卷 681-697页

作者： Di Hu Shouli Yi Di Lin Suping Gao Ting Lei Wenji Li Tingdan Xu Songlin Jiang School of Fine Arts and Calligraphy Sichuan Normal UniversityChengdu610000China Sichuan Certification and Accreditation Association Chengdu610000China College of Landscape Architecture Sichuan Agricultural UniversityChengdu610000China School of Design Chongqing Industry Polytechnic CollegeChongqing401120China

In plants,heteromorphic self-incompatibility(HetSI)is a strategy for avoiding self-pollination and promoting outcrossing,and during this process,numerous protein-protein interaction events occur between the pistil and pollen.Previous studies in Primula and Fagopyrum that focused on HetSI systems have provided interesting insights;however,the molecular mechanism underlying HetSI remains largely unknown.In this study,we profiled the proteome of Plumbago auriculata stigmas before and after self-incompatible(SI)and self-compatible(SC)pollination.Comparative analyses were conducted by 4D-DIA(Four-dimensional data independent acquisition),a promising technology that increases the sensitivity and reduces the spectral complexity of proteomic analysis by adding a fourth dimension,ion mobility.The results revealed 33387 peptides and 5311 proteins in all samples.The pathways in which the differentially expressed proteins(DEPs)identified in the P×P(Pin style self-pollinated with pin pollen)vs.PS(Pin style)and T×T(Thrum style self-pollinated with thrum pollen)vs.TS(Thrum style)comparisons were significantly enriched were biosynthesis of secondary metabolites and pentose and glucuronate interconversions.In the P×T(Pin style cross-pollinated with thrum pollen)vs.PS and T×P(Thrum style cross-pollinated with pin pollen)vs.TS comparison,the top three pathways were biosynthesis of secondary metabolites,pentose and glucuronate interconversions,and phenylpropanoid biosynthesis.The phenylpropanoid biosynthesis,cutin,suberine and wax biosynthesis,and flavonoid biosynthesis pathways were enriched in the P×T vs.P×P comparison,and starch and sucrose metabolism,glycerophospholipid metabolism,and alpha-linolenic acid metabolism were abundant in the T×T vs.T×P comparison.The enriched pathways between PS and TS were the biosynthesis of secondary metabolites,phenylpropanoid biosynthesis,and pentose and glucuronate interconversion.Self-incompatibility protein S1(SI S1),Mitogen-activated protein kinase 3/4(MPK3/4),Mitogen-activated protein kinas

关键词： Heteromorphic self-incompatibility Plumbago auriculata proteomics 4D-DIA

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proteomics of adjacent-to-tumor samples uncovers clinically relevant biological events in hepatocellular carcinoma

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National Science Review 2023年第8期10卷 88-104页

作者： Hongwen Zhu Youpei Lin Dayun Lu Shisheng Wang Yuejia Liu Liangqing Dong Qian Meng Jing Gao Yuqiu Wang Nixue Song Yuying Suo Li Ding Pei Wang Bing Zhang Daming Gao Jia Fan Qiang Gao Hu Zhou Department of Analytical Chemistry State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor ResearchShanghai Institute of Materia Medica Chinese Academy of Sciences 2. Department of Liver Surgery and TransplantationLiver Cancer InstituteZhongshan Hospital and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education Fudan University School of Chinese Materia Medica Nanjing University of Chinese Medicine Institutes for Systems Genetics and NHC Key Lab of Transplant Engineering and Immunology Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application West China Hospital Sichuan University University of Chinese Academy of Sciences Department of Medicine McDonnell Genome Institute Siteman Cancer Center Washington University Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai Lester and Sue Smith Breast Center Department of Molecular and Human Genetics Baylor College of Medicine State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences

Normal adjacent tissues(NATs) of hepatocellular carcinoma(HCC) differ from healthy liver tissues and their heterogeneity may contain biological information associated with disease occurrence and clinical outcome that has yet to be fully evaluated at the proteomic level. This study provides a detailed description of the heterogeneity of NATs and the differences between NATs and healthy livers and revealed that molecular features of tumor subgroups in HCC were partially reflected in their respective NATs. Proteomic data classified HCC NATs into two subtypes(Subtypes 1 and 2), and Subtype 2 was associated with poor prognosis and high-risk recurrence. The pathway and immune features of these two subtypes were characterized. Proteomic differences between the two NAT subtypes and healthy liver tissues were further investigated using data-independent acquisition mass spectrometry, revealing the early molecular alterations associated with the progression from healthy livers to NATs. This study provides a high-quality resource for HCC researchers and clinicians and may significantly expand the knowledge of tumor NATs to eventually benefit clinical practice.

关键词： proteomics hepatocellular carcinoma normal tissue adjacent to tumor heterogeneity

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