Transgenic overexpression of Reg protein caused gastric cell proliferation and differentiation along parietal cell and chief cell lineages

Abstract

Reg (regenerating gene product) was originally identified as a growth factor involved in pancreatic regeneration. During the healing course of gastric erosion, Reg expression is highly increased in the enterochromaffinlike (ECL) cells surrounding the ulcer crater, suggesting its role as a regulator of gastric mucosal regeneration. However, there has been no direct in vivo evidence of a growth-promoting role of Reg for the gastric mucosal cells. In the current study, Reg-transgenic mice were created and gastric mucosa were analysed for histological changes. Transgenic mice showed a marked increase in the thickness of the fundic mucosa. Anti-proliferating cell nuclear antigen (PCNA) staining of the fundic mucosa demonstrated the enlargement of the proliferating neck zone and the lower PCNA-negative zone. Histological analysis employing antibodies against cell-type markers revealed expansion of the chief cell and parietal cell populations and no change in the number of surface mucus-producing cells, ECL cells, or G cells. In conclusion, Reg has a growth-promoting effect on gastric progenitor cells and an activity to direct the differentiation of the cells into chief cell and parietal cell lineages. This was in contrast to other factors, all of which had been shown to drive differentiation towards mucus producing cells in vivo. In the injured gastric mucosa, Reg may play a unique and important part in the reconstruction of the properly organized mucosal architecture.

Reg I-knockout mice reveal its role in regulation of cell growth that is required in generation and maintenance of the villous structure of small intestine

“…In addition to the role of Reg I in the pancreas, we have demonstrated that Reg I functions as a growth factor in gastric cells and is involved in gastric mucosal regeneration (Asahara et al, 1996;Fukui et al, 1998;Kazumori et al, 2000). Recently, we generated Reg I-transgenic mice, which showed that Reg I is a key regulatory molecule for the maintenance of the growth axis of the gastric glands (Miyaoka et al, 2004). Gastric glands are tubular structures that are aligned perpendicular to the gastric lumen, which harbors stem cells in a shallow area relatively close to the lumen.…”

“…The stem cells migrate either upward toward the lumen, forming the surface mucous cells, or downward toward the bottom, forming mainly parietal cells and chief cells, the major functional population of the gastric gland. In the gastric mucosa of the Reg I-transgenic mice, there was an apparent preferential expansion of the chief cells and parietal cell linage and elongation of the lower portion of the gastric glands, suggesting that Reg I might be a regulator for downward migration and differentiation along the growth axis (Miyaoka et al, 2004). This was in contrast to other growth factors, which had been shown to drive differentiation toward surface mucous cells in transgenic mouse models (Dempsey et al, 1992;Takagi et al, 1992;Sharp et al, 1995).…”

In vivo evidence for the role of RegI in gastric regeneration: transgenic overexpression of RegI accelerates the healing of experimental gastric ulcers

“…As described in our previous report, 8 the vector used to express the rat RegI protein was constructed by modifying the plasmid pEGFP-N1 (Promega, Madison, WI, USA), which contains the green fluorescent protein (GFP) gene under the control of the human cytomegalovirus (CMV) immediate early promoter. The CMV promoter region spans from nucleotide number 1 to 589 in the plasmid vector.…”

“…8 Previous reports 9,10 showed that the mouse stomach, in contrast to the rat stomach, shows very low levels of RegI expression, providing an ideal experimental system with which to test the effects of the regI transgene. Tg mice of 3 weeks old, just finishing the period of gastric gland morphogenesis, showed apparent gastric mucosal hypertrophy and elevated expression of a cell proliferation marker, compared with littermate controls.…”

“…Tg mice of 3 weeks old, just finishing the period of gastric gland morphogenesis, showed apparent gastric mucosal hypertrophy and elevated expression of a cell proliferation marker, compared with littermate controls. 8 Thus, we now have an experimental system in which to test the function of RegI in gastric ulcer healing (gastric mucosal 'regeneration') in vivo. In this study, using Reg-Tg mice, we asked whether the transgene accelerates the healing of experimental gastric ulcers.…”