Expression of growth regulatory genes in a scid mouse-human model of intestinal epithelial regeneration

Analysis of human intestinal epithelial regeneration has been limited. This study has used a novel SCID mouse-human model to test the hypothesis that distinct stages of human intestinal epithelial regeneration are accompanied by differential expression of growth regulatory genes. Disaggregated epith elium, which included crypt cell aggregates,was isolated from human fetal s mall intestine and transplanted subcutaneously in SCID mice. This method in duced a coordinated regeneration response and enabled temporal separation o f cell populations at different stages of histogenesis and cytodifferentiat ion. Graft epithelium was identified using a specific anti-human monoclonal antibody (MAb 5D3) against cytokeratins 8 and 18. functional epithelial li neages were identified by appropriate markers. Growth regulatory genes rele vant to proliferation and apoptosis, including Bcl-2, p53 and Ki67, were as sayed at different stages of regeneration. During early regeneration, Bcl-2 , p53, and Ki67 were expressed throughout the epithelial compartment, On co mpletion of regeneration, these genes were expressed only in crypt epitheli um and mere absent from villi. This study has established a novel SCID mous e-human model of intestinal epithelial regeneration, During early regenerat ion, increased Bcl-2 and Ki67 expression may indicate suppression of apopto sis and enhanced proliferation respectively, consistent with expansion of t he stem cell fraction. The p53 gene may influence pathways of differentiati on during regeneration, analogous to its role during development. Copyright (C) 1999 John Wiley & sons, Ltd.