The small intestine as a model for evaluating adult tissue stem cell drug targets 1

Abstract.  Adult tissue stem cells are defined and some current controversies are discussed. These crucial cells are responsible for all cell production in renewing tissues, and play a vital role in tissue regeneration. Although reliable stem cell markers are generally unavailable for adult epithelial tissues, the small intestinal crypts are an excellent in vivo model system to study stem cells. Within this tissue, the stem cells have a very well‐defined cell position, allowing accurate definition of stem cell specific events. Clonal regeneration assays for the small intestine allow stem cell survival and functional competence to be studied. The ultimate lineage ancestor stem cells are extremely efficiently protected from genetic damage, which accounts for the low cancer incidence in this tissue. Some of the regulatory networks governing stem and transit cell behaviour are beginning to be understood and it is postulated that p53 plays a crucial role in these processes.

[1]  Sunil Badve,et al.  Derivation of hepatocytes from bone marrow cells in mice after radiation‐induced myeloablation , 2000, Hepatology.

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

[3]  H. Okano,et al.  Musashi, a neural RNA-binding protein required for drosophila adult external sensory organ development , 1994, Neuron.

[4]  U. Paulus,et al.  A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation , 1992, Cell proliferation.

[5]  M. Loeffler,et al.  Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. , 1990, Development.

[6]  Tony Pawson,et al.  β-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/EphrinB , 2002, Cell.

[7]  C. Hillyer Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2001 .

[8]  Xin Wang,et al.  Purified hematopoietic stem cells can differentiate into hepatocytes in vivo , 2000, Nature Medicine.

[9]  John Cairns,et al.  Mutation selection and the natural history of cancer , 1975, Nature.

[10]  J. Sherley,et al.  Cosegregation of chromosomes containing immortal DNA strands in cells that cycle with asymmetric stem cell kinetics. , 2002, Cancer research.

[11]  J. Cairns Somatic stem cells and the kinetics of mutagenesis and carcinogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[12]  C. Potten,et al.  Stem cells in gastrointestinal epithelium: numbers, characteristics and death. , 1998, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[13]  H. Withers,et al.  Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. , 1970, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[14]  C. Potten,et al.  The intestinal epithelial stem cell: the mucosal governor , 1997, International journal of experimental pathology.

[15]  J. Cairns,et al.  The segregation of DNA in epithelial stem cells , 1978, Cell.

[16]  M. Grompe,et al.  Kinetics of liver repopulation after bone marrow transplantation. , 2002, The American journal of pathology.

[17]  R. Poulsom,et al.  Cell differentiation: Hepatocytes from non-hepatic adult stem cells , 2000, Nature.

[18]  C. Potten,et al.  The relationship between ionizing radiation-induced apoptosis and stem cells in the small and large intestine. , 1998, British Journal of Cancer.

[19]  T. Slaga,et al.  Evidence that the centrally and peripherally located cells in the murine epidermal proliferative unit are two distinct cell populations. , 1985, The Journal of investigative dermatology.

[20]  J. Bickenbach Identification and behavior of label-retaining cells in oral mucosa and skin. , 1981, Journal of dental research.

[21]  H. Okano,et al.  Musashi1: An Evolutionally Conserved Marker for CNS Progenitor Cells Including Neural Stem Cells , 2000, Developmental Neuroscience.

[22]  J. Till,et al.  A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. , 1961, Radiation research.

[23]  Christopher S Potten,et al.  Intestinal stem cells protect their genome by selective segregation of template DNA strands. , 2002, Journal of cell science.

[24]  Gerard Brady,et al.  Crowd control in the crypt , 2002, Nature Medicine.

[25]  Hideyuki Okano,et al.  Identification of a putative intestinal stem cell and early lineage marker; musashi-1. , 2003, Differentiation; research in biological diversity.

[26]  J. Hendry,et al.  Cell death (apoptosis) in the mouse small intestine after low doses: effects of dose-rate, 14.7 MeV neutrons, and 600 MeV (maximum energy) neutrons. , 1982, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[27]  J. Hendry,et al.  Differential survival of murine small and large intestinal crypts following ionizing radiation. , 1997, International journal of radiation biology.

[28]  C. Potten,et al.  Extreme sensitivity of some intestinal crypt cells to X and γ irradiation , 1977, Nature.

[29]  Christopher S Potten,et al.  The intestinal epithelial stem cell. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[30]  K. Mikoshiba,et al.  The Neural RNA-Binding Protein Musashi1 Translationally Regulates Mammalian numb Gene Expression by Interacting with Its mRNA , 2001, Molecular and Cellular Biology.