Abstract LB-139: Tissue stem cell specific enhancer element identifies two types of stem cells in the corpus epithelium of the stomach

Abstract

Abstract The activity of a previously identified hematopoietic stem cell marker, Runx1 enhancer element (eR1) (Ng et al, Stem Cells 28, 1869-1881, 2010), was found to mark tissue stem cells of multiple organs. In corpus of stomach, stem cells are known to reside at isthmus, upper part of gastric unit. They are undifferentiated cells. However, molecular approach to these stem cells has not been described. Recently, fully differentiated Pepsinogen expressing chief cells at the bottom of gastric unit were shown to have tissue regeneration activity, and these cell were named reserve stem cells (Stange et al, Cell 155, 357-368, 2013). In our study, eR1 was shown to mark stem cells of both types. Lineage tracing experiments demonstrated that both types of stem cells continuously gave rise to mature cells to maintain the gastric unit. Manipulation of gene expression in a stem cell-specific manner in the stomach, especially in undifferentiated stem cells, is a long sought-after approach to study gastric carcinogenesis. We crossed transgenic mouse carrying eR1-CreERT2 with LSL-K-rasG12D mice. After tamoxifen treatment, rapid differentiation from the stem cells in the isthmus was observed, mainly into Muc5ac+ cells (surface epithelial cells). As a result, pseudo-pyloric metaplasia was induced which is similar to that observed in human gastritis. Acid-producing parietal cells were eliminated during this process. Rapid generation of Muc5ac+ cells and other phenotype are similar, but not identical, to the phenotype described in Menetrier disease which is known to be caused by excessive production of TGF-α and hyper-stimulation of EGF receptor (Reviewed in Coffey et al, J Clin Invest. 117:70-80, 2007). Menetrier disease is considered to be pre-malignant state. Activation of K-rasG12D in eR1+ chief cells also induced metaplastic lesions. In this case, pepsinogen producing chief cells robustly expressed the marker of mucous neck cells that are considered to be a precursor to chief cells. Therefore, chief cells appeared to be de-differentiated to precursor cells and acquired the stem cell property. We are using eR1 to study step-wise carcinogenesis in stomach and other organs. Citation Format: Junichi Matsuo, Shunichi Kimura, Cai Ping Koh, Md Zakir Hossain, Akihiro Yamamura, Kazuyoshi Kohu, Michiaki Unno, Jimmy Bok Yan So, Feng Zhu, Supriya Srivastava, Teh Meng, Nicholas Barker, Khay Guan Yeoh, Motomi Osato, Yoshiaki Ito. Tissue stem cell specific enhancer element identifies two types of stem cells in the corpus epithelium of the stomach. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-139. doi:10.1158/1538-7445.AM2015-LB-139