Loss of Indian Hedgehog activates multiple aspects of a wound healing response in the mouse intestine.
OBJECTIVE
Indian Hedgehog (Ihh) is expressed by the differentiated epithelial cells of the small intestine and signals to the mesenchyme where it induces unidentified factors that negatively regulate intestinal epithelial precursor cell fate. Recently, genetic variants in the Hh pathway have been linked to the development of inflammatory bowel disease.


METHODS
We deleted Ihh from the small intestinal epithelium in adult mice using Cyp1a1-CreIhh(fl/fl) conditional Ihh mutant mice. Intestines were examined by immunohistochemistry, in situ hybridization, and real-time polymerase chain reaction.


RESULTS
Deletion of Ihh from the intestinal epithelium initially resulted in a proliferative response of the intestinal epithelium with lengthening and fissioning of crypts and increased Wnt signaling. The epithelial proliferative response was associated with loss of bone morphogenetic protein and Activin signaling from the epithelium of the villus and crypts, respectively. At the same stage we observed a substantial influx of fibroblasts and macrophages into the villus core with increased mesenchymal transforming growth factor-β signaling and deposition of extracellular matrix proteins. Prolonged loss of Ihh resulted in progressive leukocyte infiltration of the crypt area, blunting and loss of villi, and the development of intestinal fibrosis.


CONCLUSIONS
Loss of Ihh initiates several events that are characteristic of an intestinal wound repair response. Prolonged loss resulted in progressive inflammation, mucosal damage, and the development of intestinal fibrosis. Ihh is a signal derived from the superficial epithelial cells that may act as a critical indicator of epithelial integrity.
van Dop
Willemijn A
WA
Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands. w.a.vandop@amc.uva.nl
Heijmans
Jarom
J
Büller
Nikè V J A
NV
Snoek
Susanne A
SA
Rosekrans
Sanne L
SL
Wassenberg
Elisabeth A
EA
van den Bergh Weerman
Marius A
MA
Lanske
Beate
B
Clarke
Alan R
AR
Winton
Douglas J
DJ
Wijgerde
Mark
M
Offerhaus
G Johan
GJ
Hommes
Daan W
DW
Hardwick
James C
JC
de Jonge
Wouter J
WJ
Biemond
Izak
I
van den Brink
Gijs R
GR
D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000235:genetics*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D007421:Intestine, Small / Q000293:injuries / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
D053823:Hedgehog Proteins; D016212:Transforming Growth Factor beta; C514061:ihh protein, mouse