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.

Public Health Relevance

Gastroparesis and other gastroenteropathies occur frequently in patients with diabetes mellitus but lack curative therapy and represent a significant health care burden. Degeneration and loss of electrical pacemaker cells residing within the gastrointestinal muscular wall play a key role in these disorders. This project will investigate how these cells can be replaced or regenerated from tissue stem cells by manipulating mechanisms that control stem cell renewal and differentiation, and by facilitating the production of differentiating signals arising from the tissue microenvironment.

National Institute of Health (NIH)
Research Project (R01)
Project #
Application #
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Hamilton, Frank A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Wang, Yuexiang; Marino-Enriquez, Adrian; Bennett, Richard R et al. (2014) Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet 46:601-6
Asuzu, D T; Hayashi, Y; Izbeki, F et al. (2011) Generalized neuromuscular hypoplasia, reduced smooth muscle myosin and altered gut motility in the klotho model of premature aging. Neurogastroenterol Motil 23:e309-23
Stanich, Jennifer E; Gibbons, Simon J; Eisenman, Seth T et al. (2011) Ano1 as a regulator of proliferation. Am J Physiol Gastrointest Liver Physiol 301:G1044-51
Gomez-Pinilla, P J; Gibbons, S J; Sarr, M G et al. (2011) Changes in interstitial cells of cajal with age in the human stomach and colon. Neurogastroenterol Motil 23:36-44
Parkman, H P; Camilleri, M; Farrugia, G et al. (2010) Gastroparesis and functional dyspepsia: excerpts from the AGA/ANMS meeting. Neurogastroenterol Motil 22:113-33
Bardsley, Michael R; Horvath, Viktor J; Asuzu, David T et al. (2010) Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. Gastroenterology 139:942-52
Izbeki, Ferenc; Asuzu, David T; Lorincz, Andrea et al. (2010) Loss of Kitlow progenitors, reduced stem cell factor and high oxidative stress underlie gastric dysfunction in progeric mice. J Physiol 588:3101-17
Gomez-Pinilla, Pedro J; Gibbons, Simon J; Bardsley, Michael R et al. (2009) Ano1 is a selective marker of interstitial cells of Cajal in the human and mouse gastrointestinal tract. Am J Physiol Gastrointest Liver Physiol 296:G1370-81
Ordog, T; Hayashi, Y; Gibbons, S J (2009) Cellular pathogenesis of diabetic gastroenteropathy. Minerva Gastroenterol Dietol 55:315-43
Soffer, E; Abell, T; Lin, Z et al. (2009) Review article: gastric electrical stimulation for gastroparesis--physiological foundations, technical aspects and clinical implications. Aliment Pharmacol Ther 30:681-94

Showing the most recent 10 out of 22 publications