Abstract
ABSTRACTMouse fetal intestinal progenitors lining the epithelium prior to villogenesis grow as spheroids when cultured ex vivo and express the transmembrane glycoprotein Trop2 as a marker. Here, we report the characterization of Trop2-expressing cells from fetal pre-glandular stomach, growing as immortal undifferentiated spheroids, and their relationship with gastric development and regeneration. Trop2+ cells generating gastric spheroids differed from adult glandular Lgr5+ stem cells, but appeared highly related to fetal intestinal spheroids. Although they shared a common spheroid signature, intestinal and gastric fetal spheroid-generating cells expressed organ-specific transcription factors and were committed to intestinal and glandular gastric differentiation, respectively. Trop2 expression was transient during glandular stomach development, being lost at the onset of gland formation, whereas it persisted in the squamous forestomach. Undetectable under homeostasis, Trop2 was strongly re-expressed in glands after acute Lgr5+ stem cell ablation or following indomethacin-induced injury. These highly proliferative reactive adult Trop2+ cells exhibited a transcriptome displaying similarity with that of gastric embryonic Trop2+ cells, suggesting that epithelium regeneration in adult stomach glands involves the partial re-expression of a fetal genetic program.
Highlights
Adult epithelia lining the digestive tract rely on a panel of stem cells to self-renew and maintain tissue homeostasis following injury
Gastric Trop2-expressing fetal cells grow as immortal spheroids ex vivo Fetal progenitors lining the intestinal epithelium before cytodifferentiation were previously identified as Trop2-expressing
In the present study, we have shown that Trop2 marks fetal gastric epithelial cells and is re-expressed, together with other fetal markers, in cells contributing to regeneration of the glandular stomach following epithelial injury
Summary
Adult epithelia lining the digestive tract rely on a panel of stem cells to self-renew and maintain tissue homeostasis following injury. Actively cycling cells behaving as stem/ progenitor cells are essentially located in the isthmus of the corpus glands. Their differentiation generates pit and neck cells secreting mucins, parietal cells that produce hydrochloric acid, as well as chief cells and endocrine cells producing zymogens and hormones, respectively (Hoffmann, 2015). Actively cycling stem cells are present in the bottom of the glands and express leucine-rich repeat G proteincoupled receptor 5 (Lgr). Actively cycling stem cells are present in the bottom of the glands and express leucine-rich repeat G proteincoupled receptor 5 (Lgr5) They give rise mainly to mucus-secreting and endocrine cells (Barker et al, 2010). A pool of rare quiescent villin-traced cells has been reported to be reactivated upon interferon gamma treatment, leading to repopulation of entire antral gland units; their molecular signature remains unknown (Qiao et al, 2007)
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