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 e nzyme markers of gastrointestinal development and function. Little is know about the mechanisms that regulate the induction of these enzymes during hu man fetal development, as these events occur primarily in utero. The presen t 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 borde r alkaline phosphatase, aminopeptidase-N, alpha -glucosidase, lactase-phlor izin hydrolase, and dipeptidyl peptidase IV enzyme activities were measured quantitatively using scanning microdensitometry along the crypt-villus axe s of fetal, xenograft, and pediatric (median age, 34 mo) biopsies. Ectopic grafting of fetal jejunum closely recapitulated the development of these en zymes in utero, with alkaline phosphatase, aminopeptidase-N, alpha -glucosi dase, and dipeptidyl peptidase IV enzyme activities closely matching the sp atiotemporal distribution and levels recorded in pediatric duodenal biopsie s. Lactase-phlorizin hydrolase was the only enzyme not to reach values reco rded in pediatric brush border membranes, although activities were signific antly (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 t rans-acting factors that promote human epithelial differentiation and funct ion in vivo. Characterization of such agents may be of potential therapeuti c use in the treatment of diseases associated with gastrointestinal immatur ity, notably necrotizing enterocolitis.