Developmental regulation of intestinal epithelial hydrolase activity in human fetal jejunal xenografts maintained in severe-combined immunodeficient mice.
Intestinal epithelial brush border hydrolases are important and sensitive enzyme markers of gastrointestinal development and function. Little is know about the mechanisms that regulate the induction of these enzymes during human fetal development, as these events occur primarily in utero. The present work used ectopically grafted human fetal jejunal xenografts (median age,13.3 wk of gestation), maintained in severe-combined immunodeficient mice, to study the differential expression of five different hydrolases after 10 wk of xenotransplantation. The spatio-temporal distribution of brush border alkaline phosphatase, aminopeptidase-N, alpha-glucosidase, lactase-phlorizin hydrolase, and dipeptidyl peptidase IV enzyme activities were measured quantitatively using scanning microdensitometry along the crypt-villus axes of fetal, xenograft, and pediatric (median age, 34 mo) biopsies. Ectopic grafting of fetal jejunum closely recapitulated the development of these enzymes in utero, with alkaline phosphatase, aminopeptidase-N, alpha-glucosidase, and dipeptidyl peptidase IV enzyme activities closely matching the spatio-temporal distribution and levels recorded in pediatric duodenal biopsies. Lactase-phlorizin hydrolase was the only enzyme not to reach values recorded in pediatric brush border membranes, although activities were significantly (5.6-fold) higher than in pretransplanted fetal bowel. Human jejunal xenografts therefore demonstrate an appropriate developmental induction of brush border hydrolase activity and may represent a useful model to study trans-acting factors that promote human epithelial differentiation and function in vivo. Characterization of such agents may be of potential therapeutic use in the treatment of diseases associated with gastrointestinal immaturity, notably necrotizing enterocolitis.
Savidge
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TC
Developmental Gastroenterology Laboratory, Combined Program in Pediatric Gastroenterology and Nutrition, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA 02129, U.S.A. savidge@helix.mgh.harvard.edu
Lowe
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DC
Walker
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WA
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D018826:CD13 Antigens / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004848:Epithelium / Q000201:enzymology; D005260:Female; D016332:Fetal Tissue Transplantation; D006651:Histocytochemistry; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D007583:Jejunum / Q000196:embryology / Q000201:enzymology* / Q000637:transplantation*; D010694:Lactase-Phlorizin Hydrolase / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008871:Microvilli / Q000201:enzymology; D014183:Transplantation, Heterologous; D000520:alpha-Glucosidases / Q000378:metabolism
D006867:Hydrolases; D000469:Alkaline Phosphatase; D000520:alpha-Glucosidases; D010694:Lactase-Phlorizin Hydrolase; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4