REGULATION OF ATROPHY-INDUCED PROGENITOR CELLS IN THE GASTRIC CORPUS

Summary

Principal Investigator: Jason C Mills
Abstract: DESCRIPTION (provided by applicant): Despite recent breakthroughs in identifying prospective stem cell markers (e.g., LGR5) in the intestines and the gastric antrum, relatively little is known about the stem cells of the gastric (body) corpus epithelium. Our overall goal is t better characterize the corpus stem cell under normal conditions and in response to injury. Preliminary data show that the selective estrogen receptor modulator tamoxifen causes ablation of nearly all parietal cells, the acid-secreting lineage, in the mouse stomach within 3 days. Within 6 hours, parietal cells begin to die (atrophy), and progenitor cells in the isthmal stem cel niche of corpus gastric units begin to expand in response. We further find that: 1) the cell surface protein CD44 is required for normal stem cell homeostasis, because proliferation is halved in Cd44-/- relative to wildtype mice;and 2) CD44 marks the expanding isthmal progenitor population. CD44 activates STAT3 and is induced by ERK signaling. We show here that ERK and STAT3 are activated in early expanding progenitors, and levels of the ERK-induced transcription factor EGR1 peak at 3 days, in concert with maximal progenitor expansion. We hypothesize that parietal cell death leads to signals that activate the ERK pathway in isthmal stem/progenitor cells, which causes increased CD44 expression and increased proliferation. In Aim 1, we will determine whether ERK signaling is required for normal stem cell homeostasis and atrophy-induced expansion using both ERK pharmacological inhibition and pedigrees of mice with deficient (Egr1-/-) and overactive (Nab2-/-) ERK. In Aim 2, we will determine whether CD44 is required or sufficient for atrophy-induced progenitor expansion. We will examine kinetics of stem cell expansion in Cd44-/- mice, and we will either activate CD44 in wildtype mice [unreadable]tamoxifen by injection of the CD44 ligand Hyaluronan or block CD44- Hyaluronan interactions with the inhibitor PEP-1. We will determine if CD44 induces STAT3 and/or if it is required for progenitor expansion. In Aim 3, we will isolate vehicle- and tamoxifen-treated CD44-expressing epithelial progenitor cells by FACS and laser-capture microdissection and then use RNA-Seq to generate gene expression profiles of the normal and atrophy-expanded progenitor cells that will then be integrated bioinformatically with our existing database of global gene expression in stem and progenitor cells. We will also perform limiting dilution assays to determine the stem cell frequency within the epithelial CD44 population. In humans, chronic inflammation can cause parietal cell atrophy, which in turn changes stem cell proliferation and differentiation. Atrophy predispose patients to gastric cancer, but changes in stem cells secondary to inflammation/injury are also an important and understudied aspect of adult diseases in multiple other tissues (e.g., hematopoietic stem cell differentiation changes in arthritis). Thus, the experiments proposed may help us begin to understand stem cell response to injury in multiple tissues and diseases. Finally, our new finding that the key drug tamoxifen causes gastric toxicity warrants further study in humans.
Funding Period: 2012-09-11 - 2017-06-30
more information: NIH RePORT

Top Publications

  1. pmc Autoimmune gastritis mediated by CD4+ T cells promotes the development of gastric cancer
    Thanh Long M Nguyen
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, MO 63104, USA
    Cancer Res 73:2117-26. 2013
  2. pmc The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation
    Shradha S Khurana
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 288:16085-97. 2013
  3. pmc Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium
    Daniel E Stange
    Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, University of Dresden, 01307 Dresden, Germany
    Cell 155:357-68. 2013
  4. pmc Chronic tamoxifen use is associated with a decreased risk of intestinal metaplasia in human gastric epithelium
    Chang Mo Moon
    Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyung Dong, Jongro Gu, Seoul, 110 746, Republic of Korea
    Dig Dis Sci 59:1244-54. 2014
  5. pmc RAB26 coordinates lysosome traffic and mitochondrial localization
    Ramon U Jin
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    J Cell Sci 127:1018-32. 2014

Detail Information

Publications5

  1. pmc Autoimmune gastritis mediated by CD4+ T cells promotes the development of gastric cancer
    Thanh Long M Nguyen
    Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, MO 63104, USA
    Cancer Res 73:2117-26. 2013
    ..Our work provides the first direct evidence that AIG supports the development of gastric neoplasia and provides a useful model to study how inflammation drives gastric cancer...
  2. pmc The hyaluronic acid receptor CD44 coordinates normal and metaplastic gastric epithelial progenitor cell proliferation
    Shradha S Khurana
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 288:16085-97. 2013
    ..We further show that we can intervene pharmacologically at each signaling step in vivo to modulate proliferation...
  3. pmc Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium
    Daniel E Stange
    Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands Department of General, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, University of Dresden, 01307 Dresden, Germany
    Cell 155:357-68. 2013
    ..These observations challenge the notion that stem cell hierarchies represent a "one-way street." ..
  4. pmc Chronic tamoxifen use is associated with a decreased risk of intestinal metaplasia in human gastric epithelium
    Chang Mo Moon
    Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyung Dong, Jongro Gu, Seoul, 110 746, Republic of Korea
    Dig Dis Sci 59:1244-54. 2014
    ..Although estrogen exposure, including tamoxifen, has been studied in correlation with gastric cancer, little has been investigated about its effects on IM...
  5. pmc RAB26 coordinates lysosome traffic and mitochondrial localization
    Ramon U Jin
    Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    J Cell Sci 127:1018-32. 2014
    ..The data elucidate a novel function for RAB26 and suggest a mechanism for how cells could increase transcription of key effectors to reorganize subcellular compartments during differentiation. ..

Research Grants30

  1. CANCER CENTER SUPPORT GRANT
    TONY R HUNTER; Fiscal Year: 2013
    ....
  2. Multi-Spectral Targeted Imaging for Early Detection of Cancer in Barrett's Esopha
    Thomas D Wang; Fiscal Year: 2013
    ..The Validation &Pathology Core will provide support for validation of peptide binding activity to amplified and overexpressed gene targets in high-grade dysplasia and early adenocarcinoma. ..
  3. The UC Davis Center for Children's Enviromental Health and Disease Prevention
    JUDY A VAN DE WATER; Fiscal Year: 2013
    ....
  4. Oxyntic Atrophy and Novel Gastric Lineages
    JAMES RICHARD GOLDENRING; Fiscal Year: 2013
    ..Through these studies we will gain fundamental insights into the cellular processes that lead to the induction of metaplasia as the critical initiating step for gastric carcinogenesis. ) ..
  5. Immunobioogy for Marrow Allografts for Leukemia
    RICHARD JOHN O'REILLY; Fiscal Year: 2013
    ..The 3 cores include: Core A which provides all patient samples and evaluate grafts pre and post HSCT, Core B Biostatistics and Core C administrative support and oversight. ..
  6. The role of Hedgehog Signaling in gastric tissue homeostasis and disease
    Yana Zavros; Fiscal Year: 2013
    ..In addition, identifying the role of Hedgehog signaling in the development of neoplasia will allow for the therapeutic intervention to target the treatment or prevention of gastric cancer. ..
  7. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  8. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  9. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  10. Olfactory Epithelial Stem Cell Regulation by the Transcription Factor p63
    Nikolai Schnittke; Fiscal Year: 2013
    ..abstract_text> ..
  11. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  12. The Biology of Prostate Cancer Skeletal Metastases
    EVAN TODD KELLER; Fiscal Year: 2013
    ..This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases. ..
  13. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  14. Role of Intestinal Cell Kinase in the Intestinal Epithelium
    Zheng Fu; Fiscal Year: 2013
    ....
  15. Role of Sox2 in stomach development, regeneration and cancer
    Konrad Hochedlinger; Fiscal Year: 2013
    ....