Lgr5+ve Stem Cells Drive Self-Renewal in the Stomach and Build Long-Lived Gastric Units In Vitro

Abstract

The study of gastric epithelial homeostasis and cancer has been hampered by the lack of stem cell markers and in vitro culture methods. The Wnt target gene Lgr5 marks stem cells in the small intestine, colon, and hair follicle. Here, we investigated Lgr5 expression in the stomach and assessed the stem cell potential of the Lgr5(+ve) cells by using in vivo lineage tracing. In neonatal stomach, Lgr5 was expressed at the base of prospective corpus and pyloric glands, whereas expression in the adult was predominantly restricted to the base of mature pyloric glands. Lineage tracing revealed these Lgr5(+ve) cells to be self-renewing, multipotent stem cells responsible for the long-term renewal of the gastric epithelium. With an in vitro culture system, single Lgr5(+ve) cells efficiently generated long-lived organoids resembling mature pyloric epithelium. The Lgr5 stem cell marker and culture method described here will be invaluable tools for accelerating research into gastric epithelial renewal, inflammation/infection, and cancer.

Identification of Lineage-Uncommitted, Long-Lived, Label-Retaining Cells in Healthy Human Esophagus and Stomach, and in Metaplastic Esophagus

“…Furthermore it has also been reported that the murine small intestinal and colonic crypt base columnar cells (CBCs) expressing lgr5, are actively cycling and are able to regenerate the entire cell population. 1,[20][21] We have also shown LGR5 mRNA is expressed in LRC region of the Barrett's mucosa in man.…”

“…Fifth even the relatively simple question of the location of stem cells in the normal stomach and esophagus in man have not been previously proposed, although data is available in animal models. Despite these problems other techniques which trace lineage by genetic analyses strongly favour the likelihood of common stem cells between squamous and columnar esophageal mucosa [19][20][21][22][23][24] . The site of stem cells in BE has been more problematic [10][11][12][13][14][15] as well as the availability of true 'biomarkers' of stem cells [16][17][18] .…”

Tissue Engineering Functional Gastrointestinal Regions: The Importance of Stem and Progenitor Cells

“…The niche environment centers around the crypt base Lgr5-positive stem cells that divide into both daughter stem cells and transit-amplifying (TA) cells committed to differentiation. Although the direction of these divisions as a population is random, and the number of stem cells remains relatively constant through all divisions, it appears that location in the crypt determines whether a stem cell produces more stem cells or differentiates (Lopez-Garcia et al 2010;Snippert et al 2010;Ritsma et al 2014;Walther and Graham 2014).…”

Modeling colorectal cancer as a 3-dimensional disease in a dish: the case for drug screening using organoids, zebrafish, and fruit flies

“…2). Using combinations of these factors, organoids can be cultured from mouse stomach small intestine and large intestine [45][46][47][48][49], as well as from healthy human colon cells and CRCs [47,49,50]. Moreover, organoids can be initiated not only from rapidly cycling Lgr5 stem cells but also from slowly cycling Bmi1 stem cells [28,30,33].…”