Intestinal Cell News Volume 5.14 | Apr 26 2019

TOP STORY

Self-Organization and Symmetry Breaking in Intestinal Organoid Development

Investigators combined single-cell quantitative genomic and imaging approaches to characterize the development of intestinal organoids from single cells. They showed that their development followed a regeneration process that was driven by transient activation of the transcriptional regulator YAP1. [Nature] Abstract

(Ranked by impact factor of the journal)

Single-Cell Transcriptomes of the Regenerating Intestine Reveal a Revival Stem Cell

Researchers applied single-cell RNA sequencing to profile the regenerating mouse intestine and identified a distinct, damage-induced quiescent cell type that they termed the revival stem cell (revSC). revSCs were marked by high clusterin expression and were extremely rare under homoeostatic conditions, yet give rise—in a temporal hierarchy—to all the major cell types of the intestine, including LGR5⁺ crypt-base columnar cells. [Nature] Abstract

A Reinforcing HNF4–SMAD4 Feed-Forward Module Stabilizes Enterocyte Identity

The authors established that the transcription factor HNF4A acted redundantly with an intestine-restricted HNF4 paralog, HNF4G, to activate enhancer chromatin and upregulate the majority of transcripts enriched in the differentiated epithelium; cells failed to differentiate on double knockout of both HNF4 paralogs. [Nat Genet] Abstract

Early Life Stress Disrupts Intestinal Homeostasis via NGF-TrkA Signaling

Scientists showed that neonatal maternal separation induced expansion of intestinal stem cells and their differentiation toward secretory lineages including enterochromaffin (EC) and Paneth cells, leading to EC hyperplasia, increased serotonin production, and visceral hyperalgesia. [Nat Commun] Full Article

An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling

The authors screened the Drosophila sorting nexins and discovered that one, SH3PX1, profoundly affected gut homeostasis and lifespan. SH3PX1 restrained intestinal stem cell division through an endocytosis-autophagy network that included Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. [Dev Cell] Full Article | Graphical Abstract

CEA Expression Heterogeneity and Plasticity Confer Resistance to the CEA-Targeting Bispecific Immunotherapy Antibody Cibisatamab (CEA-TCB) in Patient-Derived Colorectal Cancer Organoids

Scientists established patient derived colorectal cancer organoids (PDOs) from multidrug-resistant metastatic CRCs. Carcino-embryonic antigen expression of PDOs was determined by FACS and sensitivity to cibisatamab immunotherapy was assessed by co-culture of colorectal cancer organoids and allogeneic CD8 T cells. [J Immunother Cancer] Full Article

Fisetin and 5-Fluorouracil: Effective Combination for PIK3CA-Mutant Colorectal Cancer

Researchers determined the effect of fisetin, 5-fluorouracil (5-FU) or their combination on PIK3CA-mutant and PIK3CA wild-type colon cancer cells by assessing cell viability, colony formation, apoptosis, and effects on PI3K/AKT/mTOR signaling. Treatment of PIK3CA-mutant cells with fisetin and 5FU reduced the expression of PI3K, phosphorylation of AKT, mTOR, its target proteins, constituents of mTOR signaling complex, and this treatment increased the phosphorylation of AMPKα. [Int J Cancer] Abstract

Inhibition of HtrA2 Alleviated Dextran Sulfate Sodium (DSS)-Induced Colitis by Preventing Necroptosis of Intestinal Epithelial Cells

Through tandem mass tag-based quantitative proteomics, HtrA2 was found to be downregulated in the colon of DSS-treated mice. UCF-101, a specific serine protease inhibitor of HtrA2, significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss and decreased mortality. UCF-101 decreased DSS-induced colonic inflammation, prevented intestinal barrier function loss and inhibited necroptosis of intestinal epithelial cells. [Cell Death Dis] Full Article

Organoid Culture Media Formulated with Growth Factors of Defined Cellular Activity

Investigators report the production of highly pure recombinant Gremlin 1 and R-spondin 1 from bacterial expression for use in organoid media. They detailed the workflow for Gremlin 1 and R-spondin 1 expression, purification, quantification of cellular activity, quality control and use in media formulated for culturing organoids derived from a number of tissues. [Sci Rep] Full Article

Loss of PKM2 in Lgr5⁺ Intestinal Stem Cells Promotes Colitis-Associated Colorectal Cancer

Loss of pyruvate kinase M2 isoform (PKM2) was associated with dominant expression of PKM1 in Lgr5⁺ intestinal stem cells and their progeny cells. Further, the organoid-forming efficiency of whole cancer cells or Lgr5⁺ cells obtained from colon polyps of PKM2^ΔLgr5-Tx mice was significantly increased when compared with PKM2^ΔLgr5-Veh mice. [Sci Rep] Full Article

Role of Lysophosphatidic Acid in Proliferation and Differentiation of Intestinal Epithelial Cells

Investigators showed that lysophosphatidic acid (LPA), instead of epidermal growth factor, robustly promoted the development of intestinal organoids prepared from the mouse small intestine. Indeed, LPA exhibited the proliferative activity of intestinal epithelial cells as well as induction of differentiation of intestinal stem cells into goblet cells, Paneth cells, and enteroendocrine cells in intestinal organoids. [PLoS One] Full Article

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Cytokine Networks in the Pathophysiology of Inflammatory Bowel Disease

The authors discuss the progression of IBD from the perspective of remodeling of cytokine networks. They place well-established and under-studied cytokine modules in the context of cellular interactions, their dynamic regulation in early and late stages of disease, and their current and potential use in the clinic. [Immunity] Full Article

The IL-23/IL-17 Pathway in Human Chronic Inflammatory Diseases—New Insight from Genetics and Targeted Therapies

Investigators review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients. [Genes Immun] Full Article

The Gut and the Inflammatory Bowel Diseases Inside-Out: The Extra-Intestinal Manifestations

The authors focused on three patterns. First, the conventional extra-intestinal manifestations localized to bone and joints, to the eye, to the biliary tree and to the skin. Second, the so-called IBD-like syndromes accompanied by bone marrow-derived anomalies of innate or acquired immunity. Third, specific disorders of the skin and of the lungs. [Minerva Gastroenterol Dietol] Abstract

Visit our reviews page to see a complete list of reviews in the intestinal cell research field.

Merck Provides Update on Phase III KEYNOTE-062 Trial Evaluating KEYTRUDA^® (Pembrolizumab) as Monotherapy and in Combination with Chemotherapy for First-Line Treatment of Patients with Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Merck announced topline findings from the final analysis of the pivotal Phase III KEYNOTE-062 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy and in combination with chemotherapy for the first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. [Merck Sharp & Dohme Corp] Press Release

Provention Bio Completes Enrollment of Phase IIa PRINCE Clinical Trial with PRV-6527 in Patients with Moderate to Severe Crohn’s Disease

Provention Bio, Inc. announced that it has completed the enrollment in its Phase IIa PRovention Investigation in Crohn’s Disease (PRINCE) clinical trial evaluating PRV-6527 in patients with moderate-to-severe Crohn’s disease. [Provention Bio, Inc.] Press Release

CStone Received IND Approval in China for Avapritinib Phase I/II Bridging Registrational Study in Patients with Advanced Gastrointestinal Stromal Tumors

CStone Pharmaceuticals announced that the National Medical Products Administration recently approved the initiation of a Phase I/II clinical trial in China evaluating avapritinib, a drug candidate discovered by the company’s partner Blueprint Medicines, in patients with unresectable or metastatic gastrointestinal stromal tumors. [CStone Pharmaceuticals] Press Release

Salix Grabs Ex-asia Rights to Mitsubishi Tanabe Autoimmune Drug

Salix Pharmaceuticals has bagged the ex-Asia rights to Mitsubishi Tanabe’s late-phase autoimmune drug, amiselimod. The Bausch Health subsidiary plans to trial the S1P receptor functional antagonist in ulcerative colitis. [Questex LLC] Press Release

Crohn’s Disease Research Set to Benefit from £1.8M Funding Boost

Helmsley has awarded a grant to aid University of Edinburgh scientists’ understanding of Crohn’s disease. This is one of the first projects in Scotland to be funded by Helmsley. The $2.3 million grant will help improve how experts monitor and determine outcomes for Crohn’s disease, a form of inflammatory bowel disease (IBD) that affects around 120,000 people in the United Kingdom. [The Leona M. and Harry B. Helmsley Charitable Trust] Press Release

US Universities Reassess Collaborations with Foreign Scientists in Wake of NIH Letters

Kuspa’s attempt to stay ahead of NIH came to naught. A few months into the audit, Baylor College of Medicine received letters from the US National Institutes of Health (NIH) asking about four scientists it believed had violated the agency’s rule requiring them to disclose all foreign ties relating to their research. [ScienceInsider] Editorial

Elsevier and Norway Agree on New Open-Access Deal

After unsuccessful negotiations between a coalition of Norwegian organizations and the academic publisher Elsevier culminated in cancelled subscriptions earlier this year, the two have successfully established a new nationwide licensing agreement. [The Scientist] Editorial

Fearing No-Deal Brexit, European Funder Orders UK Researchers to Transfer Grants

The prospect of Brexit, the United Kingdom’s departure from the European Union, has loomed long and large over researchers, but the effects on funding, so far, have been speculative. Now, a European funding agency has made a pre-emptive strike in advance of Brexit, changing a policy that directly impacts grants in the United Kingdom. [ScienceInsider] Editorial

NEW The Copenhagen Bioscience Conference on Intestinal Organoids
September 29-October 2, 2019
Copenhagen, Denmark

Visit our events page to see a complete list of events in the community.

NEW Postdoctoral Researcher – Gastrointestinal Cancer & IBD (Case Western Reserve University)

Postdoctoral Position – Functional Genomics of IBS (Wellcome Sanger Institute)

Postdoctoral Position – Oesophago-Gastric Cancer Research (University of Cambridge)

Postdoctoral Position – IBS and Autoimmune Disease (National Research Council of Canada)

Postdoctoral Position – Animal Genomics & IBD (University of Liège)

Graduate Student Position – Breast & Colorectal Cancer Research (Dalhousie University)

Postdoctoral Fellow – Inflammatory Bowel Disease Research (University of Toronto)

Postdoctoral Fellow – Functional Genomics & IBD (Wellcome Sanger Institute)

Postdoctoral & Research Associate Positions – Biology of Intestinal & Colon Stem Cells & Gastrointestinal Cancer (Johns Hopkins University)

Associate Professor – Oncology (University of California, Davis)

Postdoctoral Position – Paneth Cells (Erasmus MC Cancer Institute)

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