Altered goblet cell differentiation and surface mucus properties in Hirschsprung disease.

[hirschsprung disease]

Hirschsprung disease -associated enterocolitis (HAEC ) leads to significant mortality and morbidity , but its pathogenesis remains unknown . Changes in the colonic epithelium related to goblet cells and the luminal mucus layer have been postulated to play a key role . Here we show that the colonic epithelium of both aganglionic and ganglionic segments are altered in patients and in mice with Hirschsprung disease (HSCR ). Structurally , goblet cells were altered with increased goblet cell number and reduced intracellular mucins in the distal colon of biopsies from patients with HSCR . Endothelin receptor B (Ednrb ) mutant mice showed increased goblet cell number and size and increased cell proliferation compared to wild-type mice in aganglionic segments , and reduced goblet cell size and number in ganglionic segments . Functionally , compared to littermates , Ednrb-/- mice showed increased transepithelial resistance , reduced stool water content and similar chloride secretion in the distal colon . Transcript levels of goblet cell differentiation factors SPDEF and Math 1 were increased in the distal colon of Ednrb-/- mice . Both distal colon from Ednrb mice and biopsies from HSCR patients showed reduced Muc 4 expression as compared to controls , but similar expression of Muc 2 . Particle tracking studies showed that mucus from Ednrb-/- mice provided a more significant barrier to diffusion of 200 nm nanoparticles as compared to wild-type mice . These results suggest that aganglionosis is associated with increased goblet cell proliferation and differentiation and subsequent altered surface mucus properties , prior to the development of inflammation in the distal colon epithelium . Restoration of normal goblet cell function and mucus layer properties in the colonic epithelium may represent a therapeutic strategy for prevention of HAEC .