Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach

Leushacke, Marc; Tan, Si Hui; Wong, Angeline M.L.; Yada, Swathi; Hajamohideen, Amin; Tan, Liang Juin; Goh, Jonathan; Wong, Esther; Denil, Simon; Murakami, Kazuhiro; Barker, Nick

doi:10.1038/ncb3541

Cited by 223 publications

(328 citation statements)

References 42 publications

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“…To induce injury in the stomach, we employed a high-dose tamoxifen ("HD-Tam") injury model that has been used by us and others (Huh et al, 2012;Burkitt et al, 2017;Lee et al, 2017;Leushacke et al, 2017). HD-Tam causes loss of nearly all acid-secreting parietal cells in the body of the stomach (Figs EV1 and EV3) and induces mature, differentiated digestive-enzyme-secreting chief cells at the base of the unit to give rise to a proliferating cell population (Radyk et al, 2018).…”

Section: Diverse Organs Show Similar Changes In Metabolic Activity Dumentioning

confidence: 99%

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

et al. 2018

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In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as ; and finally reactivate mTORC1 and re-enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re-entry at S-phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome-defective mice, both metaplasia-associated gene expression changes and mTORC1-mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia- or progenitor-associated gene induction; (iii) cell cycle re-entry. We propose this program, which we term "paligenosis", is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.

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Section: Diverse Organs Show Similar Changes In Metabolic Activity Dumentioning

confidence: 99%

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

et al. 2018

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“…It is known that LGR5 + cells with properties of self-renewal are located in the gastric antrum and yield long-lived gastric units in vitro 77 . Furthermore, reserve LGR5 + cells have now been identified within mouse and human chief cells and can catalyse epithelial regeneration after injury in vitro 78 . Although LGR5 + cells do not appear to give rise to either SPEM 79 or intestinal metaplasia, they have been found to give rise to early gastric cancer 78 .…”

Section: Cell Of Originmentioning

confidence: 99%

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

2017

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Metaplasia is the replacement of one differentiated somatic cell type with another differentiated somatic cell type in the same tissue. Typically, metaplasia is triggered by environmental stimuli, which may act in concert with the deleterious effects of microorganisms and inflammation. The cell of origin for intestinal metaplasia in the oesophagus and stomach and for pancreatic acinar–ductal metaplasia has been posited through genetic mouse models and lineage tracing but has not been identified in other types of metaplasia, such as squamous metaplasia. A hallmark of metaplasia is a change in cellular identity, and this process can be regulated by transcription factors that initiate and/or maintain cellular identity, perhaps in concert with epigenetic reprogramming. Universally, metaplasia is a precursor to low-grade dysplasia, which can culminate in high-grade dysplasia and carcinoma. Improved clinical screening for and surveillance of metaplasia might lead to better prevention or early detection of dysplasia and cancer.

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“…While one group has suggested that SPEM arises from isthmal progenitor cells in the corpus [57], the vast majority of evidence from multiple groups indicates that chief cells are indeed the predominant origin of SPEM lineages in the stomach corpus. [42,47,56,58–60] Importantly, expression of pepsinogen I has been used as a marker of pseudopyloric metaplasia [61], consistent with the equivalence of pseudopyloric metaplasia with SPEM. Similarly, ductal metaplasia/PanIN lesions in the pancreas appear to evolve from reprogramming of zymogen-secreting pancreatic acinar cells [62].…”

Section: Lineage Origins Of Pyloric-type Reparative Mucous Cellsmentioning

confidence: 99%

Pyloric metaplasia, pseudopyloric metaplasia, ulcer‐associated cell lineage and spasmolytic polypeptide‐expressing metaplasia: reparative lineages in the gastrointestinal mucosa

Goldenring

2018

The Journal of Pathology

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Summary The gastrointestinal mucosae provide a critical barrier between the external and internal milieu. Thus, damage to the mucosa requires an immediate response to provide appropriate wound closure and healing. Metaplastic lineages with phenotypes similar to the mucous glands of the distal stomach or Brunner’s glands have been associated with various injurious scenarios in the stomach, small bowel and colon. These lineages have been assigned various names including pyloric metaplasia, pseudopyloric metaplasia, Ulcer-associated cell lineage (UACL) and spasmolytic polypeptide-expressing metaplasia (SPEM). A re-examination of the literature on these various forms of mucous cell metaplasia suggests that pyloric type mucosal gland lineages may provide a ubiquitous response to mucosal injury throughout the gastrointestinal tract as well as in the pancreas, esophagus and other mucosal surfaces. While the cellular origin of these putative reparative lineages likely varies in different regions of the gut, their final phenotypes may converge on a pyloric type gland dedicated to mucous secretion. In addition to their healing properties in the setting of acute injury, these pyloric type lineages may also represent precursors to neoplastic transitions in the face of chronic inflammatory influences. Further investigations are needed to determine how discrete molecular profiles relate to the origin and function of pyloric-type metaplasias previously described by histological characteristics in multiple epithelial mucosal systems in the setting of acute and chronic damage.

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Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach

Cited by 223 publications

References 42 publications

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

Regenerative proliferation of differentiated cells by mTORC 1‐dependent paligenosis

Metaplasia: tissue injury adaptation and a precursor to the dysplasia–cancer sequence

Pyloric metaplasia, pseudopyloric metaplasia, ulcer‐associated cell lineage and spasmolytic polypeptide‐expressing metaplasia: reparative lineages in the gastrointestinal mucosa

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