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To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Multiple features of potential immunosuppression were observed, including T regulatory cell (Treg) co-localization with CD8 T cells in compartmentalized tumor stroma. Finally, single-cell characterization of human tumor xenografts and in vivo CRISPR screens identified essential roles for specific tumor subpopulation-enriched gene networks in tumorigenesis. These data define cSCC tumor and stromal cell subpopulations, the spatial niches where they interact, and the communicating gene networks that they engage in cancer.
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Carcinoma de Células Escamosas/metabolismo , Genómica/métodos , Neoplasias Cutáneas/metabolismo , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Ratones , RNA-Seq , Análisis de la Célula Individual , Piel/metabolismo , Neoplasias Cutáneas/patología , Transcriptoma , Trasplante HeterólogoRESUMEN
Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification1. However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth1,2, but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period.
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Condrocitos/citología , Células Clonales/citología , Placa de Crecimiento/citología , Nicho de Células Madre/fisiología , Envejecimiento , Animales , Cartílago/citología , Autorrenovación de las Células , Células Clonales/metabolismo , Femenino , Placa de Crecimiento/metabolismo , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , RatonesRESUMEN
In situ capturing technologies add tissue context to gene expression data, with the potential of providing a greater understanding of complex biological systems. However, splicing variants and full-length sequence heterogeneity cannot be characterized at spatial resolution with current transcriptome profiling methods. To that end, we introduce spatial isoform transcriptomics (SiT), an explorative method for characterizing spatial isoform variation and sequence heterogeneity using long-read sequencing. We show in mouse brain how SiT can be used to profile isoform expression and sequence heterogeneity in different areas of the tissue. SiT reveals regional isoform switching of Plp1 gene between different layers of the olfactory bulb, and the use of external single-cell data allows the nomination of cell types expressing each isoform. Furthermore, SiT identifies differential isoform usage for several major genes implicated in brain function (Snap25, Bin1, Gnas) that are independently validated by in situ sequencing. SiT also provides for the first time an in-depth A-to-I RNA editing map of the adult mouse brain. Data exploration can be performed through an online resource (https://www.isomics.eu), where isoform expression and RNA editing can be visualized in a spatial context.
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Empalme Alternativo , Perfilación de la Expresión Génica , Animales , Ratones , Análisis de Secuencia de ARN/métodos , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Perfilación de la Expresión Génica/métodos , Expresión Génica , TranscriptomaRESUMEN
Spiders produce nature's toughest fiber using renewable components at ambient temperatures and with water as solvent, making it highly interesting to replicate for the materials industry. Despite this, much remains to be understood about the bioprocessing and composition of spider silk fibers. Here, we identify 18 proteins that make up the spiders' strongest silk type, the major ampullate fiber. Single-cell RNA sequencing and spatial transcriptomics revealed that the secretory epithelium of the gland harbors six cell types. These cell types are confined to three distinct glandular zones that produce specific combinations of silk proteins. Image analysis of histological sections showed that the secretions from the three zones do not mix, and proteomics analysis revealed that these secretions form layers in the final fiber. Using a multi-omics approach, we provide substantial advancements in the understanding of the structure and function of the major ampullate silk gland as well as of the architecture and composition of the fiber it produces.
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Genómica , Proteómica , Seda , Análisis de la Célula Individual , Arañas , Transcriptoma , Arañas/metabolismo , Arañas/genética , Animales , Seda/metabolismo , Seda/química , Seda/genética , Proteómica/métodos , Genómica/métodos , Análisis de la Célula Individual/métodos , Perfilación de la Expresión Génica/métodosRESUMEN
BACKGROUND: The multikinase inhibitor sorafenib inhibits angiogenesis and tumor cell proliferation. Sorafenib targets signaling pathways involved in liver regeneration. Previous works on regenerating mouse liver show differing results. We asked to which degree different lengths of sorafenib treatment would influence liver regeneration after hepatic resection in rats. METHODS: Fischer-344 rats received intragastric injections of sorafenib (5-15 mg/kg/d), underwent a two-thirds partial hepatectomy (PH), and were sacrificed at different time points thereafter. Sorafenib treatment was stopped 0, 3, or 14 d after PH. Serum levels of aminotransferases and labeling indices of S-phase nuclei (bromodeoxyuridine and MIB-5) were analyzed, body and liver weights measured, and levels of phospho-ERK determined by Western blot. RESULTS: Sorafenib increased aminotransferases and the number of S-phase nuclei at baseline, but decreased liver weights and levels of phospho-ERK 24 h after PH. The number of S-phase nuclei and mitotic indices decreased 48 h after PH and increased 7 d after PH in animals on sorafenib treatment. Relative liver weights were restored 5 d after PH in control rats, at 7 d in animals receiving sorafenib prior to surgery, at 10 d in rats where sorafenib was stopped 3 d after surgery, and after 14 d in rats on continuous treatment. CONCLUSIONS: In this rat model, the regenerating liver adapted to the proliferation-inhibitory effect of sorafenib during continuous treatment. Sorafenib given after hepatic resection did not completely inhibit liver regeneration, but it prolonged the regenerative phase in proportion to the length of treatment.
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Hepatectomía/métodos , Regeneración Hepática/efectos de los fármacos , Hígado/cirugía , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Hígado/metabolismo , Hígado/patología , Regeneración Hepática/fisiología , Masculino , Modelos Animales , Niacinamida/farmacología , Ratas , Ratas Endogámicas F344 , Transducción de Señal/efectos de los fármacos , Sorafenib , Factores de Tiempo , Transaminasas/sangreRESUMEN
Cell therapy for Parkinson's disease has experienced substantial growth in the past decades with several ongoing clinical trials. Despite increasing refinement of differentiation protocols and standardization of the transplanted neural precursors, the transcriptomic analysis of cells in the transplant after its full maturation in vivo has not been thoroughly investigated. Here, we present spatial transcriptomics analysis of fully differentiated grafts in their host tissue. Unlike earlier transcriptomics analyses using single-cell technologies, we observe that cells derived from human embryonic stem cells (hESCs) in the grafts adopt mature dopaminergic signatures. We show that the presence of phenotypic dopaminergic genes, which were found to be differentially expressed in the transplants, is concentrated toward the edges of the grafts, in agreement with the immunohistochemical analyses. Deconvolution shows dopamine neurons being the dominating cell type in many features beneath the graft area. These findings further support the preferred environmental niche of TH-positive cells and confirm their dopaminergic phenotype through the presence of multiple dopaminergic markers.
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BACKGROUND: In rat, the first 18-24 h after partial hepatectomy (PH) are characterized by an acute-phase reaction, after which liver regeneration predominates. Interleukin-6 (IL-6) induces the iron hormone hepcidin, which blocks iron uptake and may compromise iron uptake in the growing liver. The expressions of hepcidin and the iron-regulatory pathway of hepcidin gene expression during the late phase of liver regeneration are unknown. AIM: To characterize the expression pattern of hepcidin and the iron-sensing pathway of hepcidin regulation during liver regeneration. METHODS: Rats were subjected to PH or sham operation. Liver weights, number of S-phase nuclei, and serum levels of iron and IL-6 were determined. Messenger-RNA levels of hepcidin, ferritin, hemojuvelin, transferrin receptor 1 and 2, HFE, divalent metal transporter 1, ferroportin, and ceruloplasmin were determined with qPCR at different time points. Protein levels of STAT3 and SMAD4 were determined with western blot. RESULTS: During the acute-phase response, IL-6 release induced STAT3 protein and hepcidin mRNA, whereas mRNA levels of proteins in the iron-sensing pathway (HFE, hemojuvelin, and transferrin receptor 2) decreased. The mRNA levels of proteins involved in cellular iron uptake were increased and cellular iron export unchanged. During liver regeneration >24 h after PH, gene expressions in the iron-sensing pathway were continuously suppressed and hepcidin mRNA levels declined 3-7 days after surgery. CONCLUSIONS: Hepcidin gene expression peaks during the acute-phase response, but a sustained down-regulation of the iron-sensing pathway of hepcidin regulation gradually reduces hepcidin gene expression until regeneration is complete, thereby promoting iron mobilization to the regenerating liver.
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Péptidos Catiónicos Antimicrobianos/genética , Regeneración Hepática/genética , Hígado/anatomía & histología , ARN Mensajero/metabolismo , Transducción de Señal/genética , Animales , Péptidos Catiónicos Antimicrobianos/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Proteínas Ligadas a GPI , Expresión Génica , Proteína de la Hemocromatosis , Hepatectomía , Hepcidinas , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Interleucina-6/sangre , Hierro/sangre , Hígado/fisiología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Tamaño de los Órganos , Ratas , Ratas Endogámicas F344 , Receptores de Transferrina/genética , Receptores de Transferrina/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Proteína Smad4/genética , Proteína Smad4/metabolismoRESUMEN
Progressive multiple sclerosis (MS) is characterized by unrelenting neurodegeneration, which causes cumulative disability and is refractory to current treatments. Drug development to prevent disease progression is an urgent clinical need yet is constrained by an incomplete understanding of its complex pathogenesis. Using spatial transcriptomics and proteomics on fresh-frozen human MS brain tissue, we identified multicellular mechanisms of progressive MS pathogenesis and traced their origin in relation to spatially distributed stages of neurodegeneration. By resolving ligand-receptor interactions in local microenvironments, we discovered defunct trophic and anti-inflammatory intercellular communications within areas of early neuronal decline. Proteins associated with neuronal damage in patient samples showed mechanistic concordance with published in vivo knockdown and central nervous system (CNS) disease models, supporting their causal role and value as potential therapeutic targets in progressive MS. Our findings provide a new framework for drug development strategies, rooted in an understanding of the complex cellular and signaling dynamics in human diseased tissue that facilitate this debilitating disease.
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Enfermedades del Sistema Nervioso Central , Esclerosis Múltiple , Enfermedades del Sistema Nervioso Central/complicaciones , Progresión de la Enfermedad , Humanos , Esclerosis Múltiple/patología , Neuronas/metabolismo , ProteómicaRESUMEN
Reconstruction of heterogeneity through single cell transcriptional profiling has greatly advanced our understanding of the spatial liver transcriptome in recent years. However, global transcriptional differences across lobular units remain elusive in physical space. Here, we apply Spatial Transcriptomics to perform transcriptomic analysis across sectioned liver tissue. We confirm that the heterogeneity in this complex tissue is predominantly determined by lobular zonation. By introducing novel computational approaches, we enable transcriptional gradient measurements between tissue structures, including several lobules in a variety of orientations. Further, our data suggests the presence of previously transcriptionally uncharacterized structures within liver tissue, contributing to the overall spatial heterogeneity of the organ. This study demonstrates how comprehensive spatial transcriptomic technologies can be used to delineate extensive spatial gene expression patterns in the liver, indicating its future impact for studies of liver function, development and regeneration as well as its potential in pre-clinical and clinical pathology.
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Heterogeneidad Genética , Hígado/metabolismo , Transcriptoma , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Células Dendríticas/citología , Células Dendríticas/metabolismo , Células Endoteliales/citología , Células Endoteliales/metabolismo , Eritroblastos/citología , Eritroblastos/metabolismo , Femenino , Perfilación de la Expresión Génica , Ontología de Genes , Hepatocitos/citología , Hepatocitos/metabolismo , Macrófagos del Hígado/citología , Macrófagos del Hígado/metabolismo , Hígado/citología , Macrófagos/citología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Anotación de Secuencia Molecular , Neutrófilos/citología , Neutrófilos/metabolismoRESUMEN
Formalin-fixed paraffin embedding (FFPE) is the most widespread long-term tissue preservation approach. Here, we report a procedure to perform genome-wide spatial analysis of mRNA in FFPE-fixed tissue sections, using well-established, commercially available methods for imaging and spatial barcoding using slides spotted with barcoded oligo(dT) probes to capture the 3' end of mRNA molecules in tissue sections. We applied this method for expression profiling and cell type mapping in coronal sections from the mouse brain to demonstrate the method's capability to delineate anatomical regions from a molecular perspective. We also profiled the spatial composition of transcriptomic signatures in two ovarian carcinosarcoma samples, exemplifying the method's potential to elucidate molecular mechanisms in heterogeneous clinical samples. Finally, we demonstrate the applicability of the assay to characterize human lung and kidney organoids and a human lung biopsy specimen infected with SARS-CoV-2. We anticipate that genome-wide spatial gene expression profiling in FFPE biospecimens will be used for retrospective analysis of biobank samples, which will facilitate longitudinal studies of biological processes and biomarker discovery.
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The RNA integrity number (RIN) is a frequently used quality metric to assess the completeness of rRNA, as a proxy for the corresponding mRNA in a tissue. Current methods operate at bulk resolution and provide a single average estimate for the whole sample. Spatial transcriptomics technologies have emerged and shown their value by placing gene expression into a tissue context, resulting in transcriptional information from all tissue regions. Thus, the ability to estimate RNA quality in situ has become of utmost importance to overcome the limitation with a bulk rRNA measurement. Here we show a new tool, the spatial RNA integrity number (sRIN) assay, to assess the rRNA completeness in a tissue wide manner at cellular resolution. We demonstrate the use of sRIN to identify spatial variation in tissue quality prior to more comprehensive spatial transcriptomics workflows.
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ARN Mensajero/análisis , Análisis Espacial , Transcriptoma , Línea Celular Tumoral , HumanosRESUMEN
Paralysis occurring in amyotrophic lateral sclerosis (ALS) results from denervation of skeletal muscle as a consequence of motor neuron degeneration. Interactions between motor neurons and glia contribute to motor neuron loss, but the spatiotemporal ordering of molecular events that drive these processes in intact spinal tissue remains poorly understood. Here, we use spatial transcriptomics to obtain gene expression measurements of mouse spinal cords over the course of disease, as well as of postmortem tissue from ALS patients, to characterize the underlying molecular mechanisms in ALS. We identify pathway dynamics, distinguish regional differences between microglia and astrocyte populations at early time points, and discern perturbations in several transcriptional pathways shared between murine models of ALS and human postmortem spinal cords.
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Esclerosis Amiotrófica Lateral/genética , Expresión Génica , Neuronas Motoras/metabolismo , Médula Espinal/metabolismo , Esclerosis Amiotrófica Lateral/patología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Humanos , Ratones , Microglía/metabolismo , Microglía/patología , Neuronas Motoras/patología , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Degeneración Nerviosa/genética , Degeneración Nerviosa/fisiopatología , Neuroglía/metabolismo , Neuroglía/patología , Cambios Post Mortem , Análisis Espacio-Temporal , Médula Espinal/patología , TranscriptomaRESUMEN
Spatial resolution of gene expression enables gene expression events to be pinpointed to a specific location in biological tissue. Spatially resolved gene expression in tissue sections is traditionally analyzed using immunohistochemistry (IHC) or in situ hybridization (ISH). These technologies are invaluable tools for pathologists and molecular biologists; however, their throughput is limited to the analysis of only a few genes at a time. Recent advances in RNA sequencing (RNA-seq) have made it possible to obtain unbiased high-throughput gene expression data in bulk. Spatial Transcriptomics combines the benefits of traditional spatially resolved technologies with the massive throughput of RNA-seq. Here, we present a protocol describing how to apply the Spatial Transcriptomics technology to mammalian tissue. This protocol combines histological staining and spatially resolved RNA-seq data from intact tissue sections. Once suitable tissue-specific conditions have been established, library construction and sequencing can be completed in ~5-6 d. Data processing takes a few hours, with the exact timing dependent on the sequencing depth. Our method requires no special instruments and can be performed in any laboratory with access to a cryostat, microscope and next-generation sequencing.
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Código de Barras del ADN Taxonómico/métodos , Bulbo Olfatorio/metabolismo , ARN/genética , Análisis de Matrices Tisulares/métodos , Transcriptoma , Animales , Código de Barras del ADN Taxonómico/instrumentación , Biblioteca de Genes , Secuenciación de Nucleótidos de Alto Rendimiento , Ratones , Microtomía , Bulbo Olfatorio/ultraestructura , ARN/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Microextracción en Fase Sólida/métodos , Coloración y Etiquetado/métodos , Análisis de Matrices Tisulares/instrumentación , Fijación del Tejido/métodosRESUMEN
Periodontitis is a highly prevalent chronic inflammatory disease of the periodontium, leading ultimately to tooth loss. In order to characterize the gene expression of periodontitis-affected gingival tissue, we have here simultaneously quantified and localized gene expression in periodontal tissue using spatial transcriptomics, combining RNA sequencing with histological analysis. Our analyses revealed distinct clusters of gene expression, which were identified to correspond to epithelium, inflamed areas of connective tissue, and non-inflamed areas of connective tissue. Moreover, 92 genes were identified as significantly up-regulated in inflamed areas of the gingival connective tissue compared to non-inflamed tissue. Among these, immunoglobulin lambda-like polypeptide 5 (IGLL5), signal sequence receptor subunit 4 (SSR4), marginal zone B and B1 cell specific protein (MZB1), and X-box binding protein 1 (XBP1) were the four most highly up-regulated genes. These genes were also verified as significantly higher expressed in gingival tissue of patients with periodontitis compared to healthy controls, using reverse transcription quantitative polymerase chain reaction. Moreover, the protein expressions of up-regulated genes were verified in gingival biopsies by immunohistochemistry. In summary, in this study, we report distinct gene expression signatures within periodontitis-affected gingival tissue, as well as specific genes that are up-regulated in inflamed areas compared to non-inflamed areas of gingival tissue. The results obtained from this study may add novel information on the genes and cell types contributing to pathogenesis of the chronic inflammatory disease periodontitis.
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Encía/metabolismo , Periodontitis/metabolismo , Periodoncio/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Biopsia , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Citocinas/genética , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Receptores Citoplasmáticos y Nucleares/genética , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Péptidos/genética , Receptores de Péptidos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transcriptoma/genética , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
Sequencing the nucleic acid content of individual cells or specific biological samples is becoming increasingly common. This drives the need for robust, scalable and automated library preparation protocols. Furthermore, an increased understanding of tissue heterogeneity has lead to the development of several unique sequencing protocols that aim to retain or infer spatial context. In this study, a protocol for retaining spatial information of transcripts has been adapted to run on a robotic workstation. The method spatial transcriptomics is evaluated in terms of robustness and variability through the preparation of reference RNA, as well as through preparation and sequencing of six replicate sections of a gingival tissue biopsy from a patient with periodontitis. The results are reduced technical variability between replicates and a higher throughput, processing four times more samples with less than a third of the hands on time, compared to the standard protocol.
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Automatización de Laboratorios , Código de Barras del ADN Taxonómico , Biblioteca de Genes , Encía , Periodontitis/genética , ARN , Humanos , Periodontitis/metabolismo , ARN/química , ARN/genética , ARN/aislamiento & purificación , ARN/metabolismoRESUMEN
Single-cell transcriptome analysis overcomes problems inherently associated with averaging gene expression measurements in bulk analysis. However, single-cell analysis is currently challenging in terms of cost, throughput and robustness. Here, we present a method enabling massive microarray-based barcoding of expression patterns in single cells, termed MASC-seq. This technology enables both imaging and high-throughput single-cell analysis, characterizing thousands of single-cell transcriptomes per day at a low cost (0.13 USD/cell), which is two orders of magnitude less than commercially available systems. Our novel approach provides data in a rapid and simple way. Therefore, MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide critical insights into disease development and other biological processes.
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Biotecnología/métodos , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de la Célula Individual/métodos , Animales , Células Cultivadas , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Células MCF-7 , Ratones , Células 3T3 NIHRESUMEN
Analysis of the pattern of proteins or messengerRNAs (mRNAs) in histological tissue sections is a cornerstone in biomedical research and diagnostics. This typically involves the visualization of a few proteins or expressed genes at a time. We have devised a strategy, which we call "spatial transcriptomics," that allows visualization and quantitative analysis of the transcriptome with spatial resolution in individual tissue sections. By positioning histological sections on arrayed reverse transcription primers with unique positional barcodes, we demonstrate high-quality RNA-sequencing data with maintained two-dimensional positional information from the mouse brain and human breast cancer. Spatial transcriptomics provides quantitative gene expression data and visualization of the distribution of mRNAs within tissue sections and enables novel types of bioinformatics analyses, valuable in research and diagnostics.
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Perfilación de la Expresión Génica/métodos , Análisis de Secuencia de ARN/métodos , Transcriptoma , Animales , Encéfalo/metabolismo , Neoplasias de la Mama/metabolismo , ADN Complementario/biosíntesis , Femenino , Humanos , Ratones , Especificidad de Órganos , ARN Mensajero/metabolismoRESUMEN
Selenium in supra-nutritional doses is tumour-preventative in animal models and in humans. In this work, we have compared the effect of sodium selenite on tumour growth in a rat hepatocarcinogenesis model with the effect of sodium selenite on the regeneration of liver mass after partial hepatectomy. In the tumour model, 5 µg/mL sodium selenite in the drinking water reduced the rate of tumour growth for up to 12 months after initiation; the volume fraction of liver cancers was 14±4% with a mean bromodeoxyuridine-index of 19±11% in the treated rats compared to a volume fraction of 26±7% with a mean bromodeoxyuridine-index of 42±27% in the control rats. Despite its efficacy in reducing tumour growth, 5 µg/mL sodium selenite treatment did not affect the gain of liver mass or the rate of cell proliferation after partial hepatectomy. In the regenerating livers, the activity of the cytosolic selenoenzyme thioredoxin reductase (TrxR1) was briefly and transiently increased, an increase further potentiated by sodium selenite. TrxR1 was selectively over expressed in proliferating liver tumours in relation to the surrounding liver tissue in the tumour model, as shown using immunohistochemistry analyses. We suggest that sodium selenite is a suitable candidate for liver cancer prevention in patients with chronic liver diseases that are dependent on sustained liver regeneration due to its differential effects on neoplastic and regenerative cell proliferation. Furthermore, the over expression of TrxR1 in liver neoplasia can only partly be explained by increased growth.