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spatial transcriptomics combined with single-nucleus RNA sequencing reveals glial cell heterogeneity in the human spinal cord

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Neural Regeneration Research 2025年第11期20卷 3302-3316页

作者： Yali Chen Yiyong Wei Jin Liu Tao Zhu Cheng Zhou Donghang Zhang Department of Anesthesiology West China HospitalSichuan UniversityChengduSichuan ProvinceChina Laboratory of Anesthesia and Critical Care Medicine National-Local Joint Engineering Research Center of Translational Medicine of AnesthesiologyWest China HospitalSichuan UniversityChengduSichuan ProvinceChina Department of Anesthesiology Longgang District Maternity&Child Healthcare Hospital of Shenzhen City(Longgang Maternity and Child Institute of Shantou University Medical College)ShenzhenGuangdong ProvinceChina Department of Anesthesiology Affiliated Hospital of Zunyi Medical UniversityZunyiGuizhou ProvinceChina

Glial cells play crucial roles in regulating physiological and pathological functions,including sensation,the response to infection and acute injury,and chronic neurodegenerative *** cells include astrocytes,microglia,and oligodendrocytes in the central nervous system,and satellite glial cells and Schwann cells in the peripheral nervous *** the greater understanding of glial cell types and functional heterogeneity achieved through single-cell and single-nucleus RNA sequencing in animal models,few studies have investigated the transcriptomic profiles of glial cells in the human spinal ***,we used high-throughput single-nucleus RNA sequencing and spatial transcriptomics to map the cellular and molecular heterogeneity of astrocytes,microglia,and oligodendrocytes in the human spinal *** explore the conservation and divergence across species,we compared these findings with those from *** the human spinal cord,astrocytes,microglia,and oligodendrocytes were each divided into six distinct transcriptomic *** the mouse spinal cord,astrocytes,microglia,and oligodendrocytes were divided into five,four,and five distinct transcriptomic subclusters,*** comparative results revealed substantial heterogeneity in all glial cell types between humans and ***,we detected sex differences in gene expression in human spinal cord glial ***,in all astrocyte subtypes,the levels of NEAT1 and CHI3L1 were higher in males than in females,whereas the levels of CST3 were lower in males than in *** all microglial subtypes,all differentially expressed genes were located on the sex *** addition to sex-specific gene differences,the levels of MT-ND4,MT2A,MT-ATP6,MT-CO3,MT-ND2,MT-ND3,and MT-CO_(2) in all spinal cord oligodendrocyte subtypes were higher in females than in ***,the present dataset extensively characterizes glial cell heterogeneity and offers a valuable resource for explo

关键词： astrocyte glial cell human microglia oligodendrocyte sex differentiation single-nucleus RNA sequencing spatial transcriptomics species variation spinal cord

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spatial transcriptomics of gastric cancer brain metastasis reveals atypical vasculature strategies with supportive immune profiles

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Gastroenterology Report 2024年第1期12卷 336-347页

作者： Kaijing Liu Ying Wang Chunhua Wang Chengcheng Guo Dun Zhang Yu Zhong Lin Yin Yunxin Lu Furong Liu Yang Zhang Dongsheng Zhang Department of Medical Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China State Key Laboratory of Oncology in South China Sun Yat-sen UniversityGuangzhouGuangdongP.R.China Department of Radiation Oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China Department of Pathology Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China Department of Neurosurgery/Neuro-oncology Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China AccuraMed Technology(Guangzhou)Co. LtdGuangzhouGuangdongP.R.China Department of Clinical Research Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China Integrated Traditional Chinese and Western Medicine Research Center Sun Yat-sen University Cancer CenterGuangzhouGuangdongP.R.China

Background:Gastric cancer brain metastasis(GCBM)represents a rare but highly aggressive *** cancer cells are highly heterogeneous and differentially remodels brain vasculature and immune microenvironments,which affects the treatment effectiveness and patient *** study aimed to investigate the spatial interactions among different cell components,espe-cially the vasculature system and the brain microenvironment of GCBM ***:We used digital spatial profiling to examine 140 regions composing tumor,immune,and brain tissues from three GCBM *** data with spatial information were analyzed for tissue areas related to different blood recruitment *** validation,independent analysis of patient bulk transcriptomic data and in vivo single-cell transcriptomic data were ***:Angiogenesis and blood vessel co-option co-existed within the same GCBM *** with high epithelial-mesenchymal transition and an enhanced transcriptomic gene signature composed of CTNNB1,SPARC,VIM,SMAD3,SMAD4,TGFB1,TGFB2,and TGFB3 were more prone to adopt blood vessel co-option than *** macrophage infiltration,angiogenic chemokines,and NAMPT were found in angiogenic areas,while increased T cells,T cell activating cytokines,and reduced NAMPT were found in vessel co-option ***,angiogenesis was enriched at the tumor edge,which showed higher DMBT1 expres-sion than the tumor ***:This study mapped the orchestrated spatial characteristics of tumor and immunological compositions that support the conventional and atypical vascularization strategies in *** data provided molecular insights for more effective combinations of anti-vascular and immune therapies.

关键词： gastric cancer brain metastases spatial transcriptomics angiogenesis blood vessel co-option tumor microenvironment

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spatial transcriptomics: Biotechnologies, Computational Tools, and Neuroscience Applications

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SMALL METHODS 2025年第0期 e2401107页

作者： Wang, Qianwen Zhu, Hongyuan Deng, Lin Xu, Shuangbin Xie, Wenqin Li, Ming Wang, Rui Tie, Liang Zhan, Li Yu, Guangchuang Southern Med Univ Sch Basic Med Sci Dept Bioinformat Guangzhou 510515 Peoples R China

spatial transcriptomics (ST) represents a revolutionary approach in molecular biology, providing unprecedented insights into the spatial organization of gene expression within tissues. This review aims to elucidate advancements in ST technologies, their computational tools, and their pivotal applications in neuroscience. It is begun with a historical overview, tracing the evolution from early image-based techniques to contemporary sequence-based methods. Subsequently, the computational methods essential for ST data analysis, including preprocessing, cell type annotation, spatial clustering, detection of spatially variable genes, cell-cell interaction analysis, and 3D multi-slices integration are discussed. The central focus of this review is the application of ST in neuroscience, where it has significantly contributed to understanding the brain's complexity. Through ST, researchers advance brain atlas projects, gain insights into brain development, and explore neuroimmune dysfunctions, particularly in brain tumors. Additionally, ST enhances understanding of neuronal vulnerability in neurodegenerative diseases like Alzheimer's and neuropsychiatric disorders such as schizophrenia. In conclusion, while ST has already profoundly impacted neuroscience, challenges remain issues such as enhancing sequencing technologies and developing robust computational tools. This review underscores the transformative potential of ST in neuroscience, paving the way for new therapeutic insights and advancements in brain research.

关键词： bioinformatics computational tools neuroscience spatial transcriptomics

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spatial transcriptomics at the brain-electrode interface in rat motor cortex and the relationship to recording quality

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JOURNAL OF NEURAL ENGINEERING 2024年第4期21卷 046033-046033页

作者： Whitsitt, Quentin Saxena, Akash Patel, Bella Evans, Blake M. Hunt, Bradley Purcell, Erin K. Michigan State Univ Dept Biomed Engn E Lansing MI 48824 USA Michigan State Univ Inst Quantitat Hlth Sci & Engn E Lansing MI 48824 USA Michigan State Univ Dept Elect & Comp Engn E Lansing MI 48824 USA

Study of the foreign body reaction to implanted electrodes in the brain is an important area of research for the future development of neuroprostheses and experimental electrophysiology. After electrode implantation in the brain, microglial activation, reactive astrogliosis, and neuronal cell death create an environment immediately surrounding the electrode that is significantly altered from its homeostatic state. Objective. To uncover physiological changes potentially affecting device function and longevity, spatial transcriptomics (ST) was implemented to identify changes in gene expression driven by electrode implantation and compare this differential gene expression to traditional metrics of glial reactivity, neuronal loss, and electrophysiological recording quality. Approach. For these experiments, rats were chronically implanted with functional Michigan-style microelectrode arrays, from which electrophysiological recordings (multi-unit activity, local field potential) were taken over a six-week time course. Brain tissue cryosections surrounding each electrode were then mounted for ST processing. The tissue was immunolabeled for neurons and astrocytes, which provided both a spatial reference for ST and a quantitative measure of glial fibrillary acidic protein and neuronal nuclei immunolabeling surrounding each implant. Main results. Results from rat motor cortex within 300 mu m of the implanted electrodes at 24 h, 1 week, and 6 weeks post-implantation showed up to 553 significantly differentially expressed (DE) genes between implanted and non-implanted tissue sections. Regression on the significant DE genes identified the 6-7 genes that had the strongest relationship to histological and electrophysiological metrics, revealing potential candidate biomarkers of recording quality and the tissue response to implanted electrodes. Significance. Our analysis has shed new light onto the potential mechanisms involved in the tissue response to implanted electrodes while g

关键词： spatial transcriptomics microelectrode implants foreign body reaction differential gene expression electrophysiology

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spatial transcriptomics of the Respiratory System

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ANNUAL REVIEW OF PHYSIOLOGY 2025年第1期87卷 447-470页

作者： Megas, Stathis Wilbrey-Clark, Anna Maartens, Aidan Teichmann, Sarah A. Meyer, Kerstin B. Wellcome Sanger Inst Cambridge England Univ Cambridge Cambridge Stem Cell Inst Dept Med Cambridge England GSK Resp & Immunol Res Unit Stevenage England

Over the last decade, single-cell genomics has revealed remarkable heterogeneity and plasticity of cell types in the lungs and airways. The challenge now is to understand how these cell types interact in three-dimensional space to perform lung functions, facilitating airflow and gas exchange while simultaneously providing barrier function to avoid infection. An explosion in novel spatially resolved gene expression technologies, coupled with computational tools that harness machine learning and deep learning, now promise to address this challenge. Here, we review the most commonly used spatial analysis workflows, highlighting their advantages and limitations, and outline recent developments in machine learning and artificial intelligence that will augment how we interpret spatial data. Together these technologies have the potential to transform our understanding of the respiratory system in health and disease, and we showcase studies in lung development, COVID19, lung cancer, and fibrosis where spatially resolved transcriptomics is already providing novel insights.

关键词： respiratory system lung spatial transcriptomics genomics machine learning bioinformatics

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spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders

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JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2024年第5期154卷 1216-1231页

作者： Daccache, Joseph Park, Eunsuh Junejo, Muhammad Abdelghaffar, Mariam Hwang, Erica Mohanty, Chitrasen Singh, Chandra K. Wang, Guilin Wheeler, John O. Shields, Bridget E. Nelson, Caroline A. Wang, Yiwei Damsky, William NYU Langone Hlth Dept Pathol New York NY USA Yale Sch Med Dept Dermatol 333 Cedar StLCI 501POB 208059 New Haven CT 06510 USA Royal Coll Surg Ireland Sch Med Adliya Bahrain Univ Wisconsin Dept Biostat & Med Informat Madison WI USA Univ Wisconsin Sch Med & Publ Hlth Dept Dermatol Madison WI USA Yale Sch Med Keck Microarray Shared Resource New Haven CT USA Yale Sch Med Dept Pathol New Haven CT USA

Background: Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. Objective: We sought to understand spatial gene expression characteristics in these disorders. Methods: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. Results: CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. Conclusions: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes. (J Allergy Clin Immunol 2024;154:1216-31.)

关键词： Sarcoidosis granuloma annulare necrobiosis lipoidica necrobiotic xanthogranuloma granulomatous spatial transcriptomics necrobiosis

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spatial transcriptomics drives a new era in plant research

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PLANT JOURNAL 2023年第6期116卷 1571-1581页

作者： Yin, Ruilian Xia, Keke Xu, Xun Univ Chinese Acad Sci Coll Life Sci Beijing 100049 Peoples R China BGI Res Shenzhen 518083 Guangdong Peoples R China BGI Res Guangdong Prov Key Lab Genome Read & Write Shenzhen 518120 Guangdong Peoples R China

The plant community lags far behind the animal and human fields concerning the application of single-cell methodologies. This is primarily due to the challenges associated with plant tissue dissection and the limitations of the available technologies. However, recent advances in spatial transcriptomics enable the study of single-cells derived from plant tissues from a spatial perspective. This technology is already successfully used to identify cell types, reconstruct cell-fate lineages, and reveal cell-to-cell interactions. Future technological advancements will overcome the challenges in sample processing, data analysis, and the integration of multiple-omics technologies. Thanks to spatial transcriptomics, we anticipate several plant research projects to significantly advance our understanding of critical aspects of plant biology. Detecting spatial gene expression patterns is quite important to uncover the developmental mechanism of plant tissues and organs. The development of spatial transcriptome technology opens a new era for plant science.

关键词： spatial transcriptomics single-cell resolution cell type identification developmental lineages cell-to-cell interactions single-cell multi-omics

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spatial transcriptomics in autoimmune rheumatic disease: potential clinical applications and perspectives

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INFLAMMATION AND REGENERATION 2025年第1期45卷 1-14页

作者： Miyamoto, Atsuko Tsujii Shimagami, Hiroshi Kumanogoh, Atsushi Nishide, Masayuki Osaka Univ Grad Sch Med Dept Resp Med & Clin Immunol Suita Osaka Japan Osaka Univ World Premier Int Res Ctr Initiat WPI Immunol Frontier Res Ctr Ifrec) Dept Immunopathol Suita Osaka Japan Osaka Univ Grad Sch Med Dept Adv Clin & Translat Immunol Suita Osaka Japan Osaka Univ Inst Open & Transdisciplinary Res Initiat OTRI Integrated Frontier Res Med Sci Div Suita Osaka Japan Osaka Univ Ctr Infect Dis Educ & Res CiDER Suita Osaka Japan Osaka Univ Suita Osaka Japan Osaka Univ Ctr Adv Modal & DDS CAMaD Suita Osaka Japan

spatial transcriptomics is a cutting-edge technology that analyzes gene expression at the cellular level within tissues while integrating spatial location information. This concept, which combines high-plex RNA sequencing with spatial data, emerged in the early 2010s. spatial transcriptomics has rapidly expanded with the development of technologies such as in situ hybridization, in situ sequencing, in situ spatial barcoding, and microdissection-based methods. Each technique offers advanced mapping resolution and precise spatial assessments at the single-cell level. Over the past decade, the use of spatial transcriptomics on clinical samples has enabled researchers to identify gene expressions in specific diseased foci, significantly enhancing our understanding of cellular interactions and disease processes. In the field of rheumatology, the complex and elusive pathophysiology of diseases such as rheumatoid arthritis, systemic lupus erythematosus, and Sj & ouml;gren's syndrome remains a challenge for personalized treatment. spatial transcriptomics provides insights into how different cell populations interact within disease foci, such as the synovial tissue, kidneys, and salivary glands. This review summarizes the development of spatial transcriptomics and current insights into the pathophysiology of autoimmune rheumatic diseases, focusing on immune cell distribution and cellular interactions within tissues. We also explore the potential of spatial transcriptomics from a clinical perspective and discuss the possibilities for translating this technology to the bedside.

关键词： spatial transcriptomics Single-cell transcriptome analysis Rheumatoid arthritis Systemic lupus erythematosus

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spatial transcriptomics-aided localization for single-cell transcriptomics with STALocator

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CELL SYSTEMS 2025年第2期16卷 101195页

作者： Li, Shang Shen, Qunlun Zhang, Shihua Chinese Acad Sci Acad Math & Syst Sci NCMIS CEMSRCSDS Beijing 100190 Peoples R China Univ Chinese Acad Sci Sch Math Sci Beijing 100049 Peoples R China Univ Chinese Acad Sci Hangzhou Inst Adv Study Sch Life Sci Key Lab Syst Hlth Sci Zhejiang Prov Hangzhou 310024 Peoples R China

Single-cell RNA-sequencing (scRNA-seq) techniques can measure gene expression at single-cell resolution but lack spatial information. spatial transcriptomics (ST) techniques simultaneously provide gene expression data and spatial information. However, the data quality of the spatial resolution or gene coverage is still much lower than the quality of the single-cell transcriptomics data. To this end, we develop a ST-Aided Locator for single-cell transcriptomics (STALocator) to localize single cells to corresponding ST data. Applications on simulated data showed that STALocator performed better than other localization methods. When applied to the human brain and squamous cell carcinoma data, STALocator could robustly reconstruct the relative spatial organization of critical cell populations. Moreover, STALocator could enhance gene expression patterns for Slide-seqV2 data and predict genome-wide gene expression data for fluorescence in situ hybridization (FISH) and Xenium data, leading to the identification of more spatially variable genes and more biologically relevant Gene Ontology (GO) terms compared with the raw data. A record of this paper's transparent peer review process is included in the supplemental information.

关键词： spatial transcriptomics single-cell RNA sequencing spatial localization data integration supervised auto-encoder

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spatial transcriptomics unveils estrogen-modulated immune responses and structural alterations in the ectocervical mucosa of depot medroxyprogesterone acetate users

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SCIENTIFIC REPORTS 2025年第1期15卷 1-16页

作者： Kaldhusdal, Vilde Boger, Mathias Franzen Tjernlund, Annelie Burgener, Adam D. Bradley, Frideborg Lajoie, Julie Omollo, Kenneth Kimani, Joshua Fowke, Keith Czarnewski, Paulo Broliden, Kristina Karolinska Inst Karolinska Univ Hosp Ctr Mol Med Dept Med SolnaDiv Infect Dis Bioclinicum J7 20 S-17176 Solna Sweden Case Western Reserve Univ Ctr Global Hlth & Dis Dept Pathol Cleveland OH 44106 USA Univ Manitoba Dept Obstet & Gynecol Winnipeg MB R3E 3P5 Canada Univ Manitoba Dept Med Microbiol & Infect Dis Winnipeg MB R3E 0J9 Canada Univ Nairobi Dept Med Microbiol & Immunol Kenyatta Natl Hosp Campus Nairobi *** Kenya Partners Hlth & Dev Africa Nairobi 373700506 Kenya Univ Manitoba Dept Community Hlth Sci Winnipeg MB R3E 0W3 Canada Stockholm Univ Dept Biochem & Biophys Sci Life Lab Natl Bioinformat Infrastruct Sweden S-17165 Solna Sweden

The injectable contraceptive, depot medroxyprogesterone acetate (DMPA), is associated with compromised cervical mucosal barriers. High-resolution spatial transcriptomics is applied here to reveal the spatial localization of these altered molecular markers. Ectocervical tissue samples from Kenyan sex workers using DMPA, or non-hormonal contraceptives, underwent spatial transcriptomics and gene set enrichment analyses. Integrated systemic estradiol levels and bulk tissue gene expression data from a larger cohort enhanced the study's scope. Unsupervised clustering unveiled four epithelial and seven submucosal layers, showcasing spatially restricted and diverse functional epithelial responses, and a less structured submucosal spatial ordering. DMPA associated with mucosal-wide immunoglobulin gene upregulation, verified by CD20+ B-cell immunostaining, and upregulated immune markers adjacent to the basal membrane. Downregulated genes represented spatially restricted disrupted epithelial barrier integrity and submucosal extracellular matrix dysfunction. The transcriptional profile was associated with markers of estrogen regulation. Collectively, our findings reveal estrogen-modulated distinct ectocervical transcriptional profiles associated with DMPA usage. While upregulation of immunoglobulin genes occurs throughout the mucosa, activation of innate immune responses and dysregulation of barrier integrity markers are spatially restricted. These results extend previous analyses using bulk transcriptomics and provide insights into the molecular landscape influenced by DMPA, shedding light on contraceptive effects and health implications.

关键词： DMPA spatial transcriptomics Ectocervix Hypoestrogenemia Mucosa Estrogen

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