Bmi1 marks gastric stem cells located in the isthmus in mice

Abstract

In the mammalian stomach, the isthmus has been considered as a stem cell zone. However, various locations and proliferative activities of gastric stem cells have been reported. We focused here on the stem cell marker Bmi1, a polycomb group protein, aiming to elucidate the characteristics of Bmi1‐expressing cells in the stomach and to examine their stem cell potential. We investigated the Bmi1‐expressing cell lineage in Bmi1‐CreERT; Rosa26‐YFP, LacZ or Rosa26‐Confetti mice. We examined the in vivo and ex vivo effects of Bmi1‐expressing cell ablation by using Bmi1‐CreERT; Rosa26‐iDTR mice. The Bmi1 lineage was also traced during regeneration after high‐dose tamoxifen‐, irradiation‐ and acetic acid‐induced mucosal injuries. In the lineage‐tracing experiments using low‐dose tamoxifen, Bmi1‐expressing cells in the isthmus of the gastric antrum and corpus provided progeny bidirectionally, towards both the luminal and basal sides over 6 months. In gastric organoids, Bmi1‐expressing cells also provided progeny. Ablation of Bmi1‐expressing cells resulted in impaired gastric epithelium in both mouse stomach and organoids. After high‐dose tamoxifen‐induced gastric mucosal injury, Bmi1‐expressing cell lineages expanded and fully occupied all gastric glands of the antrum and the corpus within 7 days after tamoxifen injection. After irradiation‐ and acetic acid‐induced gastric mucosal injuries, Bmi1‐expressing cells also contributed to regeneration. In conclusion, Bmi1 is a gastric stem cell marker expressed in the isthmus of the antrum and corpus. Bmi1‐expressing cells have stem cell potentials, both under physiological conditions and during regeneration after gastric mucosal injuries. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells

“…However, this hypothesis has not been validated rigorously (Willet and Mills, 2016). Based on lineage-tracing approaches, several stem cell marker genes have been proposed, including Sox2, Runx1, Lrig1, Mist1 (Bhlha15), and Bmi1 (Arnold et al., 2011, Choi et al., 2018, Hayakawa et al., 2015, Matsuo et al., 2017, Yoshioka et al., 2019). However, these markers have proven insufficient to define IsthSC identity and function.…”

Hypergastrinemia Expands Gastric ECL Cells Through CCK2R+ Progenitor Cells via ERK Activation

“… 42 , 43 In this series of studies, ECL cells appeared to first arise from undifferentiated isthmus progenitors, then migrate mostly downward while a few migrated upward from the isthmus, in a similar manner to the migration of the parietal cell lineage. 44 Although several candidate multipotent stem cells that have been identified recently in the gastric corpus are a likely source for both ECL cells and parietal cells, 15 , 16 lineage-committed progenitors that give rise to these cell types have not been well studied. Our group previously identified Tff2 -expressing progenitors that give rise to parietal, neck, and chief lineage.…”

“…14 Moreover, it recently was confirmed by lineage tracing studies, which showed that corpus stem cells can generate all epithelial lineages. 15 , 16 However, the direct cellular origin leading to the generation of ECL cell hyperplasia in response to hypergastrinemia and other perturbations has yet to be shown.…”

Gastric Stem Cells: Physiological and Pathological Perspectives

“…Lrig1 (Leucine-rich repeats and immunoglobulin-like domain 1)-marked cells are known to give rise to daughter cells, and Lrig1-expressing isthmal cells can contribute to the regeneration of parietal cells following acute gastric injury ( Choi et al, 2018 ). Bmi1-expressing cells in the isthmus of gastric antrum and corpus also provide progeny bipolarly toward luminal and basal sides, although it is not clear whether they are colocalized with other reported stem cells ( Yoshioka et al, 2019 ). These candidate markers mentioned above and their relevant studies are concisely summarized in Table 1 .…”