Lrig1 marks a population of gastric epithelial cells capable of long-term tissue maintenance and growth in vitro

The processes involved in renewal of the epithelium that lines the mouse stomach remain unclear. Apart from the cells in the isthmus, several other populations located deeper in the gastric glands have been suggested to contribute to the maintenance of the gastric epithelium. Here, we reveal that Lrig1 is expressed in the basal layer of the forestomach and the lower part of glands in the corpus and pylorus. In the glandular epithelium of the stomach, Lrig1 marks a heterogeneous population comprising mainly non-proliferative cells. Yet, fate-mapping experiments using a knock-in mouse line expressing Cre specifically in Lrig1+ cells demonstrate that these cells are able to contribute to the long-term maintenance of the gastric epithelium. Moreover, when cultured in vitro, cells expressing high level of Lrig1 have much higher organoid forming potential than the corresponding cellular populations expressing lower levels of Lrig1. Taken together, these observations show that Lrig1 is expressed primarily by differentiated cells, but that these cells can be recruited to contribute to the maintenance of the gastric epithelium. This confirms previous observations that cells located in the lower segments of gastric glands can participate in tissue replenishment.

[1]  M. Teh,et al.  Identification of Stem Cells in the Epithelium of the Stomach Corpus and Antrum of Mice. , 2017, Gastroenterology.

[2]  J. Merchant,et al.  Prospective identification of a multilineage progenitor in murine stomach epithelium. , 2007, Gastroenterology.

[3]  Alexander van Oudenaarden,et al.  Replacement of Lost Lgr5-Positive Stem Cells through Plasticity of Their Enterocyte-Lineage Daughters. , 2016, Cell stem cell.

[4]  Hans Clevers,et al.  The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. , 2002, Cell.

[5]  Bruce J. Aronow,et al.  The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor , 2012, Cell.

[6]  O. Nielsen,et al.  YAP/TAZ-Dependent Reprogramming of Colonic Epithelium Links ECM Remodeling to Tissue Regeneration , 2018, Cell Stem Cell.

[7]  Julie A. Wilkins,et al.  Myc deletion rescues Apc deficiency in the small intestine , 2007, Nature.

[8]  R. Henriksson,et al.  Is LRIG1 a Tumour Suppressor Gene at Chromosome 3p14.3? , 2002, Acta oncologica.

[9]  Berthold Göttgens,et al.  The Epidermis Comprises Autonomous Compartments Maintained by Distinct Stem Cell Populations , 2013, Cell stem cell.

[10]  K. Jensen,et al.  Modeling human disease using organotypic cultures. , 2016, Current opinion in cell biology.

[11]  H. Clevers,et al.  Differentiated Troy + Chief Cells Act as Reserve Stem Cells to Generate All Lineages of the Stomach Epithelium , 2013, Cell.

[12]  J. Barkin,et al.  Stomach , 2015, The American Journal of Gastroenterology.

[13]  V. Luria,et al.  Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase , 1998, Transgenic Research.

[14]  K. Nam,et al.  Dynamic expansion of gastric mucosal doublecortin-like kinase 1-expressing cells in response to parietal cell loss is regulated by gastrin. , 2015, The American journal of pathology.

[15]  Hans Clevers,et al.  The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells , 2002, Cell.

[16]  R. Shivdasani,et al.  Stomach development, stem cells and disease , 2016, Development.

[17]  T. Wang,et al.  TFF2 mRNA transcript expression marks a gland progenitor cell of the gastric oxyntic mucosa. , 2010, Gastroenterology.

[18]  J. Mills,et al.  Inducible activation of Cre recombinase in adult mice causes gastric epithelial atrophy, metaplasia, and regenerative changes in the absence of "floxed" alleles. , 2010, American journal of physiology. Gastrointestinal and liver physiology.

[19]  J. Mills,et al.  Isthmus Time Is Here: Runx1 Identifies Mucosal Stem Cells in the Gastric Corpus. , 2017, Gastroenterology.

[20]  C. P. Leblond,et al.  Histological Localization of Newly-formed Desoxyribonucleic Acid. , 1948, Science.

[21]  J. Pačes,et al.  Troy, a tumor necrosis factor receptor family member, interacts with lgr5 to inhibit wnt signaling in intestinal stem cells. , 2013, Gastroenterology.

[22]  H. Tomita,et al.  Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche. , 2015, Cancer cell.

[23]  Hans Clevers,et al.  Lrig1 controls intestinal stem cell homeostasis by negative regulation of ErbB signalling , 2012, Nature Cell Biology.

[24]  J. Mills,et al.  Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss. , 2016, Methods in molecular biology.

[25]  Allan R. Jones,et al.  A robust and high-throughput Cre reporting and characterization system for the whole mouse brain , 2009, Nature Neuroscience.

[26]  Fiona M Watt,et al.  Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence , 2006, Proceedings of the National Academy of Sciences.

[27]  R. Shivdasani,et al.  Gastric epithelial stem cells. , 2011, Gastroenterology.

[28]  A. Oudenaarden,et al.  Dll1+ secretory progenitor cells revert to stem cells upon crypt damage , 2012, Nature Cell Biology.

[29]  R. Coffey,et al.  Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach , 2017, Gut.

[30]  R. Henriksson,et al.  LRIG1 protein in human cells and tissues , 2003, Cell and Tissue Research.

[31]  J. Mills,et al.  Mature chief cells are cryptic progenitors for metaplasia in the stomach. , 2010, Gastroenterology.

[32]  Hans Clevers,et al.  Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. , 2011, Gastroenterology.

[33]  Hans Clevers,et al.  Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. , 2010, Cell stem cell.

[34]  Michaela Frye,et al.  Lrig1 Expression Defines a Distinct Multipotent Stem Cell Population in Mammalian Epidermis , 2009, Cell stem cell.

[35]  R. Henriksson,et al.  LRIG and cancer prognosis , 2014, Acta oncologica.

[36]  F. Watt,et al.  Lineage Tracing , 2012, Cell.

[37]  Nick Barker,et al.  Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach , 2017, Nature Cell Biology.