Hh pathway expression in human gut tissues and in inflammatory gut diseases

Abstract

Sonic hedgehog (Shh) directs early gut patterning via epithelial-mesenchymal signaling and remains expressed in endoderm-derived tissues into the adult period. In human adult gut epithelium SHH/SHH expression is strongest in basal layers, which suggests that SHH may function in the maintenance of gut epithelial stem or progenitor cells. Recent publications suggest a role for aberrant SHH/SHH expression in gut epithelial neoplasias. We hypothesized that the regenerating gut epithelium in inflammatory gut disorders would show an upregulation of SHH/SHH signaling and this abnormal signal may explain the increased incidence of neoplasia in these diseases. Archived healthy gut and inflammatory gut diseased tissues were analyzed by RNA in situ hybridization and immunohistochemistry to describe location and levels of SHH signaling. We show that SHH/SHH and its receptor PTCH1/PTCH1 expression is restricted to the glandular epithelium of the gut, in an antiluminal pattern (strongest in basal layers and weak to absent in luminal epithelium). Inflammatory diseases of the gut show dramatic increases in epithelial SHH signaling. Expression increases in inflamed glandular epithelium (including metaplastic glandular epithelium), losing its radial (crypt-villous) polarity, and expression appears upregulated and present in all epithelial cells. We also describe strong SHH/SHH and PTCH1/PTCH1 expression in intraepithelial and mucosal inflammatory cells. We suggest that SHH signaling in inflammatory diseases of the gut acts to ensure stem cell restitution of damaged mucosal epithelium. However, such signaling may also present a risk for neoplastic transformation.

Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation

“…Indeed, in several other tissues that are not known to be major developmental Hh targets (eg, breast, prostate, and colon), 36,61,62 the Hh pathway regulates tissue remodeling in response to demands imposed by metabolic and/or inflammatory stresses during adult life. 63 During chronic cholestatic liver injury induced by BDL, myofibroblastic HSC join portal fibroblasts that accumulate in the fibrous stroma near proliferating bile ductular cells. Expansion of myofibroblastic cell populations is known to result, at least in part, from bile ductular cell release of cytokines, such as PDGF-BB.…”

Regulation of adult intestinal epithelial stem cell development by thyroid hormone during Xenopus laevis metamorphosis

“…Indeed, the Shh/BMP-4 signaling pathway shown to be involved in the amphibian intestinal remodeling has also been proposed to play roles in the embryonic gut organogenesis of terrestrial vertebrates (Roberts, 2000;Zhang et al, 2001; and the postembryonic epithelial cell-renewal of the mammalian intestine (Howe et al, 2001;Madison et al, 2004;Haramis et al, 2004;He et al, 2004He et al, , 2007Batts et al, 2006). Mutations in members of this pathway are known to be associated with the numerous malformations (Litingtung et al, 1998;Ramalho-Santos et al, 2000) and diseases (Howe et al, 2001;de Santa Barbara et al, 2002Berman et al, 2003;Beachy et al, 2004;He et al, 2004;Nielsen et al, 2004). However, their precise functions, while likely conserved throughout terrestrial vertebrates, are not yet fully understood.…”

Shh/BMP‐4 signaling pathway is essential for intestinal epithelial development during Xenopus larval‐to‐adult remodeling

“…Also in the human adult intestine, Shh expression is restricted to the region corresponding to stem cells (van den Brink et al, 2002;de Santa Barbara et al, 2003) and upregulated in the neoplastic or inflammatory intestine when the stem cells compensate for the epithelial damage (Berman et al, 2003;Nielsen et al, 2004). Therefore, it seems likely that the stem cells may make their niche adequate for the new epithelial formation by expressing Shh, which in turn ) and Chordin proteins to the medium changes the proliferating activity of intestinal tissues cultured for 5 days.…”