期刊
NATURE
卷 550, 期 7677, 页码 529-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature24269
关键词
-
资金
- March of Dimes Research Grant [1-FY14-528]
- Price Family Foundation
- National Key Research and Development Program of China [2016YFA0502202]
- National Natural Science Foundation of China [81728001, 31471121, 81773394, 81302068, 81772994]
- Program for the Top Young Innovative Talents of Fujian Province
- International Collaborative Project of Fujian Province [2017I0014]
- [R01DK113144]
- [R01DK100342]
- [R01HL132996]
- [R01CA112403]
- [R01CA193455]
In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy(1-3), but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown(1-3). In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells(4). On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells(5-8). Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63(+)KRT5(+)KRT7(+)) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63(+)KRT5(+)KRT7(+) basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.
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