Shani Ben-Moshe

Bio: Shani Ben-Moshe is an academic researcher from Weizmann Institute of Science. The author has contributed to research in topics: Regeneration (biology) & Cellular differentiation. The author has an hindex of 9, co-authored 20 publications receiving 1138 citations.

Spatial heterogeneity in the mammalian liver

Abstract: Hepatocytes operate in highly structured repeating anatomical units termed liver lobules. Blood flow along the lobule radial axis creates gradients of oxygen, nutrients and hormones, which, together with morphogenetic fields, give rise to a highly variable microenvironment. In line with this spatial variability, key liver functions are expressed non-uniformly across the lobules, a phenomenon termed zonation. Technologies based on single-cell transcriptomics have constructed a global spatial map of hepatocyte gene expression in mice revealing that ~50% of hepatocyte genes are expressed in a zonated manner. This broad spatial heterogeneity suggests that hepatocytes in different lobule zones might have not only different gene expression profiles but also distinct epigenetic features, regenerative capacities, susceptibilities to damage and other functional aspects. Here, we present genomic approaches for studying liver zonation, describe the principles of liver zonation and discuss the intrinsic and extrinsic factors that dictate zonation patterns. We also explore the challenges and solutions for obtaining zonation maps of liver non-parenchymal cells. These approaches facilitate global characterization of liver function with high spatial resolution along physiological and pathological timescales. Key hepatic functions are expressed non-uniformly across liver lobules, a phenomenon termed zonation. Here, Ben-Moshe and Itzkovitz discuss the principles of liver zonation, the intrinsic and extrinsic factors that dictate zonation patterns and new genomic approaches for studying zonation of parenchymal and non-parenchymal cells

A systematic view on influenza induced host shutoff.

Abstract: Proteins carry out diverse activities in our cells. These proteins are constantly being built according to accurate instructions, which are encoded on molecules named messenger RNAs (mRNAs for short). The process of converting the instructions into proteins is called translation. Viruses infect host cells and take over the cellular machinery that is responsible for translation. This causes the cell to produce viral proteins at the expense of host proteins – a process called host shutoff. As a result, viral proteins take over the cell and the infection accelerates. There are two main strategies used by viruses to co-opt the cell’s translation machinery: either host mRNAs are destroyed, or the machines that read mRNA molecules are manipulated to read only the viral instructions. Most viruses appear to dedicate themselves to using just one of these strategies. However, evidence suggests that the Influenza A virus uses both strategies to induce host shutoff. To investigate the extent to which each of the shutoff strategies is used by the Influenza A virus, Bercovich-Kinori, Tai et al. have studied infected human lung cells. This revealed that the virus primarily reduces the amount of host mRNA in the cells to take over the mRNA pool. The host mRNAs were affected by the infection to different extents. For example, the mRNAs that coded for proteins that perform important roles for the virus, such as produce energy, were not affected by the virus. A future challenge is to find out exactly how the Influenza A virus distinguishes between different cellular mRNAs. This knowledge may help to develop new treatments for flu.

Spatial reconstruction of single enterocytes uncovers broad zonation along the intestinal villus axis

Abstract: The intestinal epithelium is a highly structured tissue composed of repeating crypt-villus units. Enterocytes, which constitute the most abundant cell type, perform the diverse tasks of absorbing a wide range of nutrients while protecting the body from the harsh bacterial-rich environment. It is unknown if these tasks are equally performed by all enterocytes or whether they are spatially zonated along the villus axis. Here, we performed whole-transcriptome measurements of laser-capture-microdissected villus segments to extract a large panel of landmark genes, expressed in a zonated manner. We used these genes to localize single sequenced enterocytes along the villus axis, thus reconstructing a global spatial expression map. We found that most enterocyte genes were zonated. Enterocytes at villi bottoms expressed an anti-bacterial Reg gene program in a microbiome-dependent manner, potentially reducing the crypt pathogen exposure. Translation, splicing and respiration genes steadily decreased in expression towards the villi tops, whereas distinct mid-top villus zones sub-specialized in the absorption of carbohydrates, peptides and fat. Enterocytes at the villi tips exhibited a unique gene-expression signature consisting of Klf4, Egfr, Neat1, Malat1, cell adhesion and purine metabolism genes. Our study exposes broad spatial heterogeneity of enterocytes, which could be important for achieving their diverse tasks.

SF-010-4 Distant metastasis occurs late during the genetic evolution of pancreatic cancer

Abstract: Metastasis, the dissemination and growth of neoplastic cells in an organ distinct from that in which they originated, is the most common cause of death in cancer patients. This is particularly true for pancreatic cancers, where most patients are diagnosed with metastatic disease and few show a sustained response to chemotherapy or radiation therapy. Whether the dismal prognosis of patients with pancreatic cancer compared to patients with other types of cancer is a result of late diagnosis or early dissemination of disease to distant organs is not known. Here we rely on data generated by sequencing the genomes of seven pancreatic cancer metastases to evaluate the clonal relationships among primary and metastatic cancers. We find that clonal populations that give rise to distant metastases are represented within the primary carcinoma, but these clones are genetically evolved from the original parental, non-metastatic clone. Thus, genetic heterogeneity of metastases reflects that within the primary carcinoma. A quantitative analysis of the timing of the genetic evolution of pancreatic cancer was performed, indicating at least a decade between the occurrence of the initiating mutation and the birth of the parental, non-metastatic founder cell. At least five more years are required for the acquisition of metastatic ability and patients die an average of two years thereafter. These data provide novel insights into the genetic features underlying pancreatic cancer progression and define a broad time window of opportunity for early detection to prevent deaths from metastatic disease.

The Microbiota-Gut-Brain Axis

Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

Gut microbiota in human metabolic health and disease.

Abstract: Observational findings achieved during the past two decades suggest that the intestinal microbiota may contribute to the metabolic health of the human host and, when aberrant, to the pathogenesis of various common metabolic disorders including obesity, type 2 diabetes, non-alcoholic liver disease, cardio-metabolic diseases and malnutrition. However, to gain a mechanistic understanding of how the gut microbiota affects host metabolism, research is moving from descriptive microbiota census analyses to cause-and-effect studies. Joint analyses of high-throughput human multi-omics data, including metagenomics and metabolomics data, together with measures of host physiology and mechanistic experiments in humans, animals and cells hold potential as initial steps in the identification of potential molecular mechanisms behind reported associations. In this Review, we discuss the current knowledge on how gut microbiota and derived microbial compounds may link to metabolism of the healthy host or to the pathogenesis of common metabolic diseases. We highlight examples of microbiota-targeted interventions aiming to optimize metabolic health, and we provide perspectives for future basic and translational investigations within the nascent and promising research field. In this Review, Fan and Pedersen discuss how the gut microbiota and derived microbial compounds may contribute to human metabolic health and to the pathogenesis of common metabolic diseases, and highlight examples of microbiota-targeted interventions aiming to optimize metabolic health.

Single-cell spatial reconstruction reveals global division of labour in the mammalian liver

Abstract: The mammalian liver consists of hexagon-shaped lobules that are radially polarized by blood flow and morphogens. Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation, but a detailed genome-wide reconstruction of this spatial division of labour has not been achieved. Here we measure the entire transcriptome of thousands of mouse liver cells and infer their lobule coordinates on the basis of a panel of zonated landmark genes, characterized with single-molecule fluorescence in situ hybridization. Using this approach, we obtain the zonation profiles of all liver genes with high spatial resolution. We find that around 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. These include a spatial order of bile acid biosynthesis enzymes that matches their position in the enzymatic cascade. Our approach can facilitate the reconstruction of similar spatial genomic blueprints for other mammalian organs.