Abstract 5186: Lineage tracing of Cytokeratin 19 labels gastric, intestinal and colonic stem cells
Authors: Asfaha Samuel , Ericksen Russell , von Burstin Johannes , Quante Michael , Shibata Wataru , Rustgi Anil K. , Wang Timothy C. 
Published: June 2012

Introduction: Tissue stem cells, characterized by multipotentiality and self renewing ability, are not readily distinguishable from other resident cells. Tissue stem cells are believed to be present in small numbers that may remain quiescent, or divide frequently as previously shown with Lgr-5+ cells. In the gastric antrum, intestine and colon, epithelial cells derived from the stem cells at the crypt base rapidly migrate up towards to the mucosal surface, whereas in the gastric corpus, stem cells located in the isthmus are believed to give rise to epithelial progenitors that undergo bipolar migration and differentiation into pit and oxyntic cell lineages. Cytokeratin 19 (K19) has been shown to be expressed in cells in the gastric isthmus and colonic and intestinal crypts. Therefore, we aimed to use the K19 gene promoter to drive Cre recombinase expression and to track the lineage of K19+ cells in an inducible fashion.

Methods: In order to recapitulate the endogenous expression pattern of K19, we used a BAC strategy and generated a transgenic mouse with a Tamoxifen inducible Cre under the control of the K19 promoter (K19-BAC-Cre-ERTM). K19CreERT2 mice were crossed to ROSA26rLacZ (or GFP) reporter mice, treated the mice with tamoxifen (4 mg/ day p.o. for 3 days) and sacrificed at various time points (3 days, 7 days, 26 weeks and 52 weeks) following tamoxifen induction.

Results: Treatment of K19CreERT2/Rosa26r mice with tamoxifen resulted in the selective marking of about 30% of gastric and intestinal glands. Following tamoxifen induction, in the corpus a few gastric pit cells near the isthmus were labeled at 3 days, whereas, all of pit cells within the labeled glands stained positively by 7 days. Consistent with the labeling of progenitor or stem cells, all pit cells within marked glands stained positively even up to 52 weeks following tamoxifen induction. In contrast, in the antrum, intestine and colon nearly all epithelial cells were labeled within 3 days following tamoxifen induction. Once again, lineage tracing of all the epithelial cells within marked glands was observed up to 52 weeks following tamoxifen induction, suggesting that K19 likely marks a common progenitor or stem cell in the antrum, intestine and colon. Interestingly, in the small intestine and antrum K19 positive cells do not overlap with Lgr5-GFP+ cells yet clearly demonstrate stem cell properties.

Conclusions. Using K19CreERT2/Rosa26r mice, we show that K19 marks pit progenitors in the gastric corpus, as well as stem cells within the antrum, intestine and colon. These findings identify a novel population of stem cells for the lineage tracing of gastric pit cells following gastric injury or cancer, and for tracing epithelial cells in the development of intestinal or colonic cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5186. doi:10.1158/1538-7445.AM2011-5186