The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach

Bibliographic Details
Main Author:	Feng, Rui
Language:	English
Published:	University of Cincinnati / OhioLINK 2014
Subjects:	Physiological Psychology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1423581156

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-ucin14235811562021-08-03T06:29:18Z The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach Feng, Rui Physiological Psychology AbstractBackground: Epithelial cell proliferation is essential for morphogenesis as well as the proper growth of the postnatal gastric mucosa. Hedgehog (Hh) homologues are recognized as morphogens that play a role in embryonic development, maintenance of normal adult gastrointestinal proliferation and differentiation and tissue regeneration. While it is known that the Hh pathway regulates cell proliferation in small intestine, colon, bone and skin tissue, the precise mechanism by which the Hh pathway mediates epithelial cell proliferation in the adult stomach is unknown. Gastrin is a gastrointestinal hormone that stimulates the growth of the gastric mucosa by regulating epithelial cell proliferation. However, the mechanism by which gastrin triggers cell proliferation is largely unknown. Loss of expression of Sonic Hedgehog (Shh) from parietal cells results in elevated gastrin levels in mice, increased expression of Indian Hedgehog (Ihh) as well as hyperproliferation of surface mucous cells. We investigated whether hypergastrinemia induces gastric epithelial proliferation by activating Ihh signaling in mice. The expression of Hh proteins is also up-regulated during repair. Although it is known that Hh signaling is important in epithelial cell proliferation during repair, the Hh responsive cells during this process are unknown. Hypothesis: Hh signaling drives gastric epithelial cell proliferation in the adult stomach and during repair. Objectives: 1) To identify the role of Ihh signaling as a mediator of gastrin-induced proliferation, 2) to identify the Hh responsive cells within the gastric epithelium in response to injury and 3) to identify the mechanism by which Hh signaling regulates epithelial proliferation at the ulcer margin during gastric repair. Major Findings: 1) In vivo studies using a mouse model with a parietal cell-specific deletion of Shh crossed onto a gastrin deficient background (PC-ShhKO/GKO mice) and in vitro studies using gastric organoids derived from PC-ShhKO/GKO mice stomachs showed that Ihh mediates gastrin-induced proliferation by signaling through Gli1 in the mesenchyme. 2) By inducing ulcers in Ptch-lacZ reporter mice and performing ß-galactosidase staining which represents Hh target gene Ptch-1 activity, we showed that Hh signaling regulates epithelial cell proliferation by targeting the Ulcer Associated Cell Lineage (UACL) glands. The Hh proliferative response was mediated by hyaluronic receptor CD44. Conclusions and Significance: In conclusion, we find that Ihh mediates gastrin-induced epithelial cell proliferation in the adult stomach. Overall, we report here that Hh signaling drives gastric epithelial cell proliferation not only during homeostasis in the adult stomach but also during gastric repair. This new knowledge advances our current understanding of the molecular mechanisms that control epithelial cell proliferation in the adult stomach. 2014 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1423581156 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1423581156 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Physiological Psychology
spellingShingle	Physiological Psychology Feng, Rui The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
author	Feng, Rui
author_facet	Feng, Rui
author_sort	Feng, Rui
title	The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
title_short	The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
title_full	The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
title_fullStr	The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
title_full_unstemmed	The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach
title_sort	role of hedgehog signaling as a regulator of epithelial proliferation in the adult stomach
publisher	University of Cincinnati / OhioLINK
publishDate	2014
url	http://rave.ohiolink.edu/etdc/view?acc_num=ucin1423581156
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The Role of Hedgehog Signaling as a Regulator of Epithelial Proliferation in the Adult Stomach

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