Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis.

The regulation of cell number in adult tissues is determined by the balance of cell production and cell loss. In the gastrointestinal tract, where there are well defined zones of proliferation and migration of both epithelial cells and associated fibroblasts, it is widely held that cell loss occurs by shedding into the gut lumen. Since the evidence for this is not compelling, we investigated the distribution and amount of apoptosis in the normal mammalian gut. In the stomach, small intestine and colon of rodents and man, there is a small number of apoptotic bodies in the epithelium and in the immediate sub-epithelial connective tissue. Engulfment by adjacent epithelial cells and sub-epithelial macrophages accounts for the removal of apoptotic bodies. Apoptotic bodies are not randomly distributed but are found towards the distal end of the known cellular migration routes of both epithelial and mesenchymal cells. Furthermore, consideration of the absolute numbers of apoptotic bodies, their rapid clearance and the dimensions of the small intestinal villi and colonic crypts indicates that the cell loss in the normal murine intestine can largely be explained on the basis of the observed apoptosis. Despite being inconspicuous in histological material, apoptosis probably accounts for the bulk of cell loss in the gut and is a central feature of the regulation of cell number in adult tissues.

[1]  A. V. Grimstone.  Molecular biology of the cell (3rd edn) , 1995 .

[2]  F. Walsh,et al.  Signal transduction events underlying neurite outgrowth stimulated by cell adhesion molecules , 1994, Current Opinion in Neurobiology.

[3]  M. Peitsch,et al.  Distribution of deoxyribonuclease I in rat tissues and its correlation to cellular turnover and apoptosis (programmed cell death). , 1994, European journal of cell biology.

[4]  S. Frisch,et al.  Disruption of epithelial cell-matrix interactions induces apoptosis , 1994, The Journal of cell biology.

[5]  C J Kemp,et al.  The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice. , 1994, Cancer research.

[6]  K. Kinzler,et al.  Association of the APC tumor suppressor protein with catenins. , 1993, Science.

[7]  F. Masiarz,et al.  Association of the APC gene product with beta-catenin. , 1993, Science.

[8]  M. Raff,et al.  Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. , 1993, Development.

[9]  M. Sporn,et al.  TGF-beta expression in the human colon: differential immunostaining along crypt epithelium. , 1993, British Journal of Cancer.

[10]  P. Hall,et al.  In situ end‐labelling detects DNA strand breaks in apoptosis and other physiological and pathological states , 1993, The Journal of pathology.

[11]  F. Lee.  Importance of apoptosis in the histopathology of drug related lesions in the large intestine. , 1993, Journal of clinical pathology.

[12]  D. Winton,et al.  A possible explanation for the differential cancer incidence in the intestine, based on distribution of the cytotoxic effects of carcinogens in the murine large bowel. , 1992, Carcinogenesis.

[13]  S. Ben‐Sasson,et al.  Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation , 1992, The Journal of cell biology.

[14]  W. Richardson,et al.  Cell death and control of cell survival in the oligodendrocyte lineage , 1992, Cell.

[15]  D. Ahnen,et al.  Regional variability of colonocyte growth and differentiation in the rat , 1992, The Anatomical record.

[16]  C. Winterford,et al.  Ultrastructure of the Rat Pancreas after Experimental Duct Ligation. II. Duct and Stromal Cell Proliferation, Differentiation, and Deletion , 1992, Pancreas.

[17]  J. Beaulieu.  Differential expression of the VLA family of integrins along the crypt-villus axis in the human small intestine. , 1992, Journal of cell science.

[18]  A. Howell,et al.  Reduction in apoptosis relative to mitosis in histologically normal epithelium accompanies fibrocystic change and carcinoma of the premenopausal human breast , 1992, The Journal of pathology.

[19]  R. Strange,et al.  Apoptotic cell death and tissue remodelling during mouse mammary gland involution. , 1992, Development.

[20]  M. Raff,et al.  Social controls on cell survival and cell death , 1992, Nature.

[21]  P. Hall,et al.  The Kinetic Organisation of Tissues , 1992 .

[22]  K. Fleming,et al.  A nude mouse xenograft model of fetal intestine development and differentiation. , 1992, Development.

[23]  G. Zajicek,et al.  [The streaming liver]. , 1991, Harefuah.

[24]  G. Zajicek,et al.  Streaming kidney , 1991, Cell proliferation.

[25]  R. Oppenheim.  Cell death during development of the nervous system. , 1991, Annual review of neuroscience.

[26]  H. Horvitz,et al.  Mechanisms and functions of cell death. , 1991, Annual review of cell biology.

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

[28]  A. Benedetti,et al.  Quantitative study of apoptosis in normal rat gastroduodenal mucosa , 1990, Journal of gastroenterology and hepatology.

[29]  H. Moses,et al.  The cell biology of transforming growth factor β , 1990 .

[30]  M. Schachner,et al.  Expression of J1/tenascin in the crypt-villus unit of adult mouse small intestine: implications for its role in epithelial cell shedding. , 1990, Development.

[31]  S. Roberts,et al.  The temporal and spatial changes in cell proliferation within the irradiated crypts of the murine small intestine. , 1990, International journal of radiation biology.

[32]  G. Zajicek,et al.  The streaming liver. III. Littoral cells accompany the streaming hepatocyte. , 2008, Liver.

[33]  A. Benedetti,et al.  A quantitative evaluation of apoptotic bodies in rat liver. , 2008, Liver.

[34]  N. Walker,et al.  Melanosis coli. A consequence of anthraquinone-induced apoptosis of colonic epithelial cells. , 1988, The American journal of pathology.

[35]  N. Walker.  Ultrastructure of the rat pancreas after experimental duct ligation. I. The role of apoptosis and intraepithelial macrophages in acinar cell deletion. , 1987, The American journal of pathology.

[36]  G. Zajicek,et al.  The streaming adrenal cortex: direct evidence of centripetal migration of adrenocytes by estimation of cell turnover rate. , 1986, The Journal of endocrinology.

[37]  G. Zajicek,et al.  The streaming submandibular gland , 1985, The Anatomical record.

[38]  Nicholas A. Wright,et al.  The biology of epithelial cell populations , 1984 .

[39]  C. P. Leblond,et al.  Migration and turnover of entero-endocrine and caveolated cells in the epithelium of the descending colon, as shown by radioautography after continuous infusion of 3H-thymidine into mice. , 1979, The American journal of anatomy.

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

[41]  J. S. Trier,et al.  Epithelial cell proliferation and migration in the developing rat gastric mucosa. , 1976, Developmental biology.

[42]  D. Levison,et al.  Atrophy and apoptosis in the cyclical human endometrium , 1976, The Journal of pathology.

[43]  C. P. Leblond,et al.  Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian Theory of the origin of the four epithelial cell types. , 1974, The American journal of anatomy.

[44]  M. Marsh,et al.  Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum. I. Structural features. , 1974, Gastroenterology.

[45]  M. Marsh,et al.  Morphology and cell proliferation of subepithelial fibroblasts in adult mouse jejunum. II. Radioautographic studies. , 1974, Gastroenterology.

[46]  F. G. Parker,et al.  The pericryptal fibroblast sheath. IV. Replication, migration, and differentiation of the subepithelial fibroblasts of the crypt and villus of the rabbit jejunum. , 1974, Gastroenterology.

[47]  P. Cotton,et al.  Gastro-Intestinal Cell Loss in Man , 1973 .

[48]  A. Wyllie,et al.  Apoptosis: A Basic Biological Phenomenon with Wide-ranging Implications in Tissue Kinetics , 1972, British Journal of Cancer.

[49]  C. P. Leblond,et al.  Argentaffin and other "endocrine" cells of the small intestine in the adult mouse. II. Renewal. , 1971, The American journal of anatomy.

[50]  B. Creamer,et al.  Cell loss from small intestinal mucosa: a morphological study 1 , 1970, Gut.

[51]  D. Croft,et al.  D.N.A. AND CELL LOSS FROM NORMAL SMALL-INTESTINAL MUCOSA: A Clinical Method of Assessing Cell Turnover , 1968 .

[52]  R. Pascal,et al.  Colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. II. Fine structural aspects of normal rabbit and human colon. , 1968, Gastroenterology.

[53]  R. Pascal,et al.  Colonic pericryptal fibroblast sheath: replication, migration, and cytodifferentiation of a mesenchymal cell system in adult tissue. I. Autoradiographic studies of normal rabbit colon. , 1968, Gastroenterology.

[54]  H. Davenport.  Physiology of the Digestive Tract , 1967 .

[55]  J. W. Saunders,et al.  Death in Embryonic Systems , 1966, Science.

[56]  Leblond Cp.  CLASSIFICATION OF CELL POPULATIONS ON THE BASIS OF THEIR PROLIFERATIVE BEHAVIOR. , 1964 .

[57]  C. P. Leblond.  CLASSIFICATION OF CELL POPULATIONS ON THE BASIS OF THEIR PROLIFERATIVE BEHAVIOR. , 1964, National Cancer Institute monograph.

[58]  The turnover and shedding of epithelial cells , 1961, Gut.

[59]  B. Creamer,et al.  The turnover and shedding of epithelial cells , 1961, Gut.

[60]  C. P. Leblond,et al.  Cell proliferation and migration as revealed by radioautography after injection of thymidine-H3 into male rats and mice. , 1960, The American journal of anatomy.

[61]  W. Walton.  Automatic Counting of Microscopic Particles , 1952, Nature.

[62]  A. Glücksmann.  CELL DEATHS IN NORMAL VERTEBRATE ONTOGENY , 1951 .

[63]  C E NEWELL,et al.  The small intestine. , 1951, The Journal of the Tennessee State Medical Association. Tennessee State Medical Association.

[64]  H. Gray.  Gray's Anatomy , 1858 .