Interstitial Cells of Cajal in Diabetic Gastropathy

Summary

Principal Investigator: TAMAS ORDOG
Abstract: DESCRIPTION (provided by applicant): Somatic stem cells residing in many organs are responsible for tissue maintenance and repair and also contribute to aging and cancer. While the role of stem cells and cell turnover is obvious in rapidly renewing tissues, their significance in the gastrointestinal neuromuscular compartment has only recently been recognized. The classic view of gastrointestinal motility disorders including diabetic gastroparesis is that they are due to impaired tissue function and degeneration of terminally differentiated cell types such as enteric neurons, smooth muscle cells and interstitial cells of Cajal (ICC). This is also reflected in current treatment modalities, which focus on symptom control and stimulation of residual function. However, these treatments are not curative and to a large extent ineffective. Recent studies demonstrating considerable plasticity of postnatal enteric neurons, smooth muscle cells and ICC indicate that this old view is untenable. We recently identified a stem cell residing in the gastric musculature of adult mice that can give rise to ICC (ICC-SC). This paradigm shift has opened entirely new opportunities to unravel the mechanisms of ICC maintenance and differentiation and to develop new, rational therapies to regenerate ICC networks from endogenous or transplanted tissue stem cells in these disorders. However, there are several barriers that must be overcome before this goal can be realized including a lack of understanding of the mechanisms that control ICC-SC self- renewal and differentiation, as well as the role of the tissue microenvironment in these processes. Therefore, the overall goals of the current project are to determine the key cell-intrinsic and cell-extrinsic factors that control ICC-SC proliferation and differentiation and to test pharmacological agents that target ICC-SC via these factors in preclinical disease models. Our first specific aim is to determine the role and mechanisms-of-action of polycomb group proteins as cell-intrinsic factors in the epigenetic control of ICC-SC maintenance and differentiation and to test the in vivo utility of indirect histone methyltransferase inhibitors to stimulate, through the inhibition of polycomb activity, the differentiation of transplanted and endogenous ICC-SC. Our second specific aim is to determine the role and molecular mechanisms-of-action of glycogen synthase kinase 3 (Gsk3) as an extrinsic factor in regulating ICC-SC through stem cell factor expression in smooth muscle cells and to determine the in vivo utility of Gsk3 inhibitors to reverse gastroparesis by supporting ICC-SC self- renewal and differentiation. We will use novel models and new technology developed in our laboratory including freshly isolated and cultured ICC-SC, transplantation of genetically labeled ICC-SC, and quantitative analysis of key stages of ICC development by flow cytometry. We will also employ state-of-the-art molecular biological and recombinant DNA techniques to study epigenetic control of gene transcription and mouse models for preclinical testing. The proposed studies will determine the mechanistic basis for, and set the stage for clinical trials of, novel pharmacological interventions for loss of ICC in motility diseases.
Funding Period: 2000-07-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis
    Viktor J Horváth
    Department of Physiology and Cell Biology, University of Nevada, Reno, Nevada, USA
    Gastroenterology 130:759-70. 2006
  2. pmc Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways
    Yujiro Hayashi
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
    PLoS ONE 8:e76822. 2013
  3. pmc Epigenetics and chromatin dynamics: a review and a paradigm for functional disorders
    T Ordog
    Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
    Neurogastroenterol Motil 24:1054-68. 2012
  4. pmc Ano1 as a regulator of proliferation
    Jennifer E Stanich
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 301:G1044-51. 2011
  5. pmc Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging
    D T Asuzu
    Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55906, USA
    Neurogastroenterol Motil 23:e309-23. 2011
  6. pmc Polycomb and the emerging epigenetics of pancreatic cancer
    Adrienne Grzenda
    Laboratory of Chromatin Dynamics and Epigenetics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    J Gastrointest Cancer 42:100-11. 2011
  7. pmc Changes in interstitial cells of cajal with age in the human stomach and colon
    P J Gomez-Pinilla
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:36-44. 2011
  8. pmc Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors
    Michael R Bardsley
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gastroenterology 139:942-52. 2010
  9. pmc Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice
    Ferenc Izbeki
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Guggenheim 10, 200 1st Street SW, Rochester, MN 55906, USA
    J Physiol 588:3101-17. 2010
  10. pmc Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting
    H P Parkman
    Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Neurogastroenterol Motil 22:113-33. 2010

Research Grants

  1. REGULATORY CASCADES IN GASTROINTESTINAL PROLIFERATION
    Klaus H Kaestner; Fiscal Year: 2013
  2. Regulating fibrosis and muscle growth in the muscular dystrophies
    Elizabeth M McNally; Fiscal Year: 2013
  3. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
  4. Mitochondrial Target for Radiation Mitigation
    Joel S Greenberger; Fiscal Year: 2013
  5. Enteric nervous system deficits in Hirschsprung ganglionic bowel
    MELISSA MUSSER; Fiscal Year: 2013
  6. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
  7. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
  8. ACTIVATORS OF MUSCLE GENES
    Helen M Blau; Fiscal Year: 2013
  9. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
  10. Regulation of Stem Cell Self-renewal and Differentiation
    Margaret T Fuller; Fiscal Year: 2013

Detail Information

Publications19

  1. ncbi Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis
    Viktor J Horváth
    Department of Physiology and Cell Biology, University of Nevada, Reno, Nevada, USA
    Gastroenterology 130:759-70. 2006
    ..Most murine gastric ICC depend on stem cell factor (SCF) signaling but can also be maintained with insulin or insulin-like growth factor-I (IGF-I). We investigated whether SCF could mediate the actions of insulin and IGF-I...
  2. pmc Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways
    Yujiro Hayashi
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
    PLoS ONE 8:e76822. 2013
    ....
  3. pmc Epigenetics and chromatin dynamics: a review and a paradigm for functional disorders
    T Ordog
    Epigenomics Translational Program, Mayo Clinic Center for Individualized Medicine, Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering and Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
    Neurogastroenterol Motil 24:1054-68. 2012
    ....
  4. pmc Ano1 as a regulator of proliferation
    Jennifer E Stanich
    Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Am J Physiol Gastrointest Liver Physiol 301:G1044-51. 2011
    ..These data led us to conclude that Ano1 regulates proliferation at the G(1)/S transition of the cell cycle and may play a role in tumorigenesis...
  5. pmc Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging
    D T Asuzu
    Enteric NeuroScience Program and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55906, USA
    Neurogastroenterol Motil 23:e309-23. 2011
    ..We also detected reduced fecal output in these animals; therefore, the aim of this study was to investigate in vivo function and cellular make-up of the small intestinal and colonic neuromuscular apparatus...
  6. pmc Polycomb and the emerging epigenetics of pancreatic cancer
    Adrienne Grzenda
    Laboratory of Chromatin Dynamics and Epigenetics, Gastroenterology Research Unit, Departments of Biochemistry and Molecular Biology, Biophysics, and Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
    J Gastrointest Cancer 42:100-11. 2011
    ..Disruption of chromatin organization can directly and indirectly precipitate genomic instability and transformation...
  7. pmc Changes in interstitial cells of cajal with age in the human stomach and colon
    P J Gomez-Pinilla
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 23:36-44. 2011
    ..The aim of this study was to determine the effect of aging on ICC number and volume in the human stomach and colon...
  8. pmc Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors
    Michael R Bardsley
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota 55905, USA
    Gastroenterology 139:942-52. 2010
    ..In mouse models we investigated whether Kit(low) ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST...
  9. pmc Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice
    Ferenc Izbeki
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Guggenheim 10, 200 1st Street SW, Rochester, MN 55906, USA
    J Physiol 588:3101-17. 2010
    ..Klotho protects ICC by preserving their precursors, limiting oxidative stress, and maintaining nutritional status and normal levels of trophic factors important for ICC differentiation...
  10. pmc Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting
    H P Parkman
    Department of Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA
    Neurogastroenterol Motil 22:113-33. 2010
    ..Similarly, the diagnostic and treatment options for these two disorders are relatively limited despite recent advances in our understanding of both disorders...
  11. pmc Cellular pathogenesis of diabetic gastroenteropathy
    T Ordog
    Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA
    Minerva Gastroenterol Dietol 55:315-43. 2009
    ..Future research should identify ways to block cytotoxic factors, support the regeneration of damaged cells and translate the experimental findings into new treatment modalities...
  12. pmc Review article: gastric electrical stimulation for gastroparesis--physiological foundations, technical aspects and clinical implications
    E Soffer
    Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
    Aliment Pharmacol Ther 30:681-94. 2009
    ..Most studies focused on the use of electrical stimulation for gastroparesis, the only approved indication for such intervention...
  13. pmc Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract
    Pedro J Gomez-Pinilla
    Enteric Neuroscience Program, Miles and Shirley Fiterman Center for Digestive Diseases and Department of Physiology and Biomedical Engineering, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
    Am J Physiol Gastrointest Liver Physiol 296:G1370-81. 2009
    ..Ano1 labels all classes of ICC and represents a highly specific marker for studying the distribution of ICC in mouse and human tissues with an advantage over Kit since it does not label mast cells...
  14. pmc Progenitors of interstitial cells of cajal in the postnatal murine stomach
    Andrea Lorincz
    Department of Physiology and Cell Biology, University of Nevada, Reno, USA
    Gastroenterology 134:1083-93. 2008
    ..Our goal was to identify ICC precursors in postnatal murine gastric muscles...
  15. doi Do we need to revise the role of interstitial cells of Cajal in gastrointestinal motility?
    TAMAS ORDOG
    Am J Physiol Gastrointest Liver Physiol 294:G368-71. 2008
  16. ncbi Interstitial cells of Cajal in diabetic gastroenteropathy
    T Ordog
    Department of Physiology and Biomedical Engineering, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA
    Neurogastroenterol Motil 20:8-18. 2008
    ..Future research should focus on the identification of the molecular and cellular mechanisms underlying ICC loss in diabetes and the translation of the experimental findings into treatments...
  17. ncbi Differential gene expression in functional classes of interstitial cells of Cajal in murine small intestine
    Hui Chen
    Department of Physiology and Cell Biology, University of Nevada, School of Medicine, Reno, NV 89557, USA
    Physiol Genomics 31:492-509. 2007
    ..Our results may lead to the identification of novel biomarkers for ICC and provide directions for further studies designed to understand ICC function in health and disease...
  18. ncbi Selective labeling and isolation of functional classes of interstitial cells of Cajal of human and murine small intestine
    Hui Chen
    Department of Physiology and Cell Biology, School of Medicine, University of Nevada Reno, Reno, NV 89557, USA
    Am J Physiol Cell Physiol 292:C497-507. 2007
    ..ICC-DMP express neurotransmitter receptors and signaling intermediate molecules that are consistent with their role in neuromuscular neurotransmission...
  19. pmc Dystrophin is a tumor suppressor in human cancers with myogenic programs
    Yuexiang Wang
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Nat Genet 46:601-6. 2014
    ..These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in the treatment of cancer...

Research Grants30

  1. REGULATORY CASCADES IN GASTROINTESTINAL PROLIFERATION
    Klaus H Kaestner; Fiscal Year: 2013
    ..In Aim 3, we will test the hypothesis that the repressive H3K27me3 mark must be removed by the histone demethylase Jmjd3 in order to allow differentiation of intestinal epithelial cells, using inducible gene deletion. ..
  2. Regulating fibrosis and muscle growth in the muscular dystrophies
    Elizabeth M McNally; Fiscal Year: 2013
    ..Core B will provide histopathological assessment of muscular dystrophy after genetic manipulation and treatments, and Core C will perform functional analysis in vivo and provide support to Core B. ..
  3. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  4. Mitochondrial Target for Radiation Mitigation
    Joel S Greenberger; Fiscal Year: 2013
    ..abstract_text> ..
  5. Enteric nervous system deficits in Hirschsprung ganglionic bowel
    MELISSA MUSSER; Fiscal Year: 2013
    ....
  6. Mechanisms of State Switching in Sleep and Sleep Apnea
    Clifford B Saper; Fiscal Year: 2013
    ..This work will help to design interventions for improving the health of patients with OSA. ..
  7. PAPOVA VIRUS TRANSFORMING MECHANISMS
    DAVID MORSE LIVINGSTON; Fiscal Year: 2013
    ..The goal of this Program is to continue to shed new light on cellular transformation events that also underpin human cancer development and generate insights that lead to new cancer therapeutic strategies. ..
  8. ACTIVATORS OF MUSCLE GENES
    Helen M Blau; Fiscal Year: 2013
    ..The molecular insights gained will increase the clinical utility of muscle stem cells and increase our understanding of muscle biology and aging. ..
  9. 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. ..
  10. Regulation of Stem Cell Self-renewal and Differentiation
    Margaret T Fuller; Fiscal Year: 2013
    ....
  11. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  12. 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. ..
  13. Cardiac Fibrillation: Mechanisms and Therapy
    James N Weiss; Fiscal Year: 2013
    ..Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease. ..
  14. Elafin Therapy for Lung Diseases
    Marlene Rabinovitch; Fiscal Year: 2013
    ..The Administrative Core facilitates exchange of information and postdoctoral training in Lung Translational Medicine, and facilitates our strategy to move elafin into clinical trial in the next cycle. ..
  15. Strategies for Improved Shock Wave Lithotripsy
    JAMES ALEXANDER MCATEER; Fiscal Year: 2013
    ..and the session can be ended * Determine the mechanism by which cavitation within a vessel causes hemorrhage * Develop numerical models to understand the role of cavitation and non-cavitational mechanisms in causing tissue damage ..
  16. Biology and Novel Therapeutics of Cardiovascular Peptides
    John C Burnett; Fiscal Year: 2013
    ..Thus, this application brings together a highly collaborative team of physician-scientists with a highly translational proposal which should lead to innovative therapeutics for cardiorenal disease. ..
  17. Electrical control of gastric motility
    Kenton M Sanders; Fiscal Year: 2013
    ..e. functional coupling) between the corpus and antrum.. New animal models of gastric arrhythmias will be studied to determine how pacemaker abnormalities affect functional coupling...