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Lesions of the mucosal lining within the stomach, known as gastric ulcers, increase the risk of gastric cancer development. The use of non-steroidal anti-inflammatory drugs (NSAIDs), infection by the pathogen Helicobacter pylori and advancing age increase the risk for ulcer disease and augment ulcer complications. The increased incidence of gastric ulcers in elderly individuals is generally attributed to decreases in defensive factors and blood flow as well as increased use of NSAIDs. Objective: To identify novel mechanisms of gastric ulcer repair to develop novel therapeutic approaches to facilitate wound healing in the aged stomach.Major findings: Identification of a role of parietal cell-derived Sonic hedgehog (Shh) secreted into circulation during gastric ulcer repair. Shh has been shown to regulate wound healing in a variety of tissue. While it is known that Shh facilitates repair, the role of Shh secreted from the gastric epithelium is unclear. To determine the role of circulating Shh during ulcer repair, ulcers were induced in mice expressing a parietal cell-specific deletion of Shh (PC-ShhKO). PC-ShhKO mice showed inhibited ulcer repair with decreased expression of circulating Shh following injury. Control mice exhibited gastric regeneration 7 days post-injury with elevated expression of Shh in circulation. Parabiosis of PC-ShhKO mice with control mice and subsequent ulceration of control and PC-ShhKO parabionts simultaneously, resulted in high levels of circulating Shh and significant ulcer healing in both parabionts. These data establish a critical role for circulating Shh in the facilitation of gastric repair. The demonstration that gastric Shh modulates the immune response during gastric regeneration.During gastric ulcer repair macrophages are suggested to promote repair. Despite its known function in tissue regeneration the role of Shh as a regulator of the immune system, specifically macrophages, during gastric healing remains unknown. Quantification of macrophages in control mice following injury showed significant influx of macrophages, which correlated with epithelial regeneration. Ulcers induced in PC-ShhKO mice and mice with inhibited hedgehog signaling in macrophages (SmoKO) exhibited delayed repair and lacked infiltrating macrophages. These data suggest that gastric Shh mediates recruitment of macrophages during gastric repair.Development of a potential therapeutic approach for the treatment of gastric ulcer repair in the aged stomach. During aging, physiological changes in the stomach result in gastric tissue that is less capable of repairing injury. Gastric organoids were transplanted into ulcerated gastric tissue of mice to determine whether normal epithelial regeneration could be restored in the aged stomach. Aged mice exhibited metaplasia surrounding the ulcerated tissue. Organoid-transplanted aged mice showed regenerated gastric glands containing organoid-derived cells. Wound healing in young mice coincided with the emergence of Spasmolytic Polypeptide/TFF2-Expressing Metaplasia (SPEM) within the ulcerated region, a response lost in the aged stomach. Organoid transplantation in aged mice led to the emergence of SPEM and gastric regeneration. Human-derived gastric organoids transplanted into immunodeficient mice engrafted within the epithelium and promoted tissue repair. These data demonstrate the potential of using gastric organoids as a basis for the development of therapy for the treatment of gastric damage. |
