Abstract
AbstractSonic Hedgehog (Shh), secreted from gastric parietal cells, contributes to the regeneration of the epithelium. The recruitment of macrophages plays a central role in the regenerative process. The mechanism that regulates macrophage recruitment in response to gastric injury is largely unknown. Here we tested the hypothesis that Shh stimulates macrophage chemotaxis to the injured epithelium and contributes to gastric regeneration. A mouse model expressing a myeloid cell-specific deletion of Smoothened (LysMcre/+;Smof/f) was generated using transgenic mice bearing loxP sites flanking the Smo gene (Smo loxP) and mice expressing a Cre recombinase transgene from the Lysozyme M locus (LysMCre). Acetic acid injury was induced in the stomachs of both control and LysMcre/+;Smof/f (SmoKO) mice and gastric epithelial regeneration and macrophage recruitment analyzed over a period of 7 days post-injury. Bone marrow-derived macrophages (BM-Mø) were collected from control and SmoKO mice. Human-derived gastric organoid/macrophage co-cultures were established, and macrophage chemotaxis measured. Compared to control mice, SmoKO animals exhibited inhibition of ulcer repair and normal epithelial regeneration, which correlated with decreased macrophage infiltration at the site of injury. Bone marrow chimera experiments using SmoKO donor cells showed that control chimera mice transplanted with SmoKO bone marrow donor cells exhibited a loss of ulcer repair, and transplantation of control bone marrow donor cells to SmoKO mice rescued epithelial cell regeneration. Histamine-stimulated Shh secretion in human organoid/macrophage co-cultures resulted in macrophage migration toward the gastric epithelium, a response that was blocked with Smo inhibitor Vismodegib. Shh-induced macrophage migration was mediated by AKT signaling. In conclusion, Shh signaling acts as a macrophage chemoattractant via a Smo-dependent mechanism during gastric epithelial regeneration in response to injury.
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Developmental Biology,Biomedical Engineering,Medicine (miscellaneous)
Reference41 articles.
1. van den Brink, G. R. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol. Rev. 87, 1343–1375 (2007).
2. van den Brink, G. R. et al. Sonic Hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract. Gut 51, 628–633 (2002).
3. Van Den Brink, G. R. et al. Sonic Hedgehog regulates gastric gland morphogenesis in man and mouse. Gastroenterology 121, 317–328 (2001).
4. Shiotani, A. et al. Re-expression of Sonic Hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. J. Cancer 121, 1182–1189 (2007).
5. Suzuki, H. et al. Down-regulation of a morphogen (Sonic Hedgehog) gradient in the gastric epithelium of Helicobacter pylori-infected Mongolian gerbils. J. Pathol. 206, 186–197 (2005).
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