Maturity and age influence chief cell ability to transdifferentiate into metaplasia

The plasticity of gastric chief cells is exemplified by their ability to transdifferentiate into spasmolytic polypeptide-expressing metaplasia (SPEM) after parietal cell loss. We sought to determine if chief cell maturity is a limiting factor in the capacity to transdifferentiate. Mist1−/− mice, previously shown to form only immature chief cells, were treated with DMP-777 or L635 to study the capability of these immature chief cells to transdifferentiate into a proliferative metaplastic lineage after acute parietal cell loss. Mist1−/− mice treated with DMP-777 showed fewer chief cell to SPEM transitions. Mist1−/− mice treated with L635 demonstrated significantly fewer proliferative SPEM cells compared with control mice. Thus immature chief cells were unable to transdifferentiate efficiently into SPEM after acute parietal cell loss. To determine whether chief cell age affects transdifferentiation into SPEM, we used tamoxifen to induce YFP expression in chief cells of Mist1CreER/+;RosaYFP mice and subsequently treated the cells with L635 to induce SPEM at 1 to 3.5 mo after tamoxifen treatment. After L635 treatment to induce acute parietal cell loss, 43% of all YFP-positive cells at 1 mo posttamoxifen were SPEM cells, of which 44% of these YFP-positive SPEM cells were proliferative. By 2 mo after tamoxifen induction, only 24% of marked SPEM cells were proliferating. However, by 3.5 mo after tamoxifen induction, only 12% of marked chief cells transdifferentiated into SPEM and none were proliferative. Thus, as chief cells age, they lose their ability to transdifferentiate into SPEM and proliferate. Therefore, both functional maturation and age limit chief cell plasticity. NEW & NOTEWORTHY Previous investigations have indicated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach arises from transdifferentiation of chief cells. Nevertheless, the intrinsic properties of chief cells that influence transdifferentiation have been largely unknown. We now report that the ability to transdifferentiate into SPEM is impaired in chief cells that lack full functional maturation, and as chief cells age, they lose their ability to transdifferentiate. Thus chief cell plasticity is dependent on both cell age and maturation.

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Differentiation of the Gastric Mucosa III. Animal models of oxyntic atrophy and metaplasia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00187.2006 ◽

2006 ◽

Vol 291 (6) ◽

pp. G999-G1004 ◽

Cited By ~ 69

Author(s):

James R. Goldenring ◽

Sachiyo Nomura

Keyword(s):

Gastric Cancer ◽

Animal Models ◽

Gastric Mucosa ◽

Chronic Inflammation ◽

Mouse Models ◽

Parietal Cell ◽

Cell Loss ◽

Chief Cells ◽

Gastric Metaplasia ◽

Spasmolytic Polypeptide

Gastric cancer in humans arises in the setting of oxyntic atrophy (parietal cell loss) and attendant hyperplastic and metaplastic lineage changes within the gastric mucosa. Helicobacter infection in mice and humans leads to spasmolytic polypeptide-expressing metaplasia (SPEM). In a number of mouse models, SPEM arises after oxyntic atrophy. In mice treated with the parietal cell toxic protonophore DMP-777, SPEM appears to arise from the transdifferentiation of chief cells. These results support the concept that intrinsic mucosal influences regulate and modulate the appearance of gastric metaplasia even in the absence of significant inflammation, whereas chronic inflammation is required for the further neoplastic transition.

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Chief cell plasticity is the origin of metaplasia following acute injury in the stomach mucosa

Gut ◽

10.1136/gutjnl-2021-325310 ◽

2021 ◽

pp. gutjnl-2021-325310

Author(s):

Brianna Caldwell ◽

Anne R Meyer ◽

Jared A Weis ◽

Amy C Engevik ◽

Eunyoung Choi

Keyword(s):

Progenitor Cells ◽

Mucosal Injury ◽

Chief Cell ◽

Lineage Tracing ◽

Acute Injury ◽

Specific Gene ◽

Cell Plasticity ◽

Chief Cells ◽

Stomach Mucosa

ObjectiveMetaplasia arises from differentiated cell types in response to injury and is considered a precursor in many cancers. Heterogeneous cell lineages are present in the reparative metaplastic mucosa with response to injury, including foveolar cells, proliferating cells and spasmolytic polypeptide-expressing metaplasia (SPEM) cells, a key metaplastic cell population. Zymogen-secreting chief cells are long-lived cells in the stomach mucosa and have been considered the origin of SPEM cells; however, a conflicting paradigm has proposed isthmal progenitor cells as an origin for SPEM.DesignGastric intrinsic factor (GIF) is a stomach tissue-specific gene and exhibits protein expression unique to mature mouse chief cells. We generated a novel chief cell-specific driver mouse allele, GIF-rtTA. GIF-GFP reporter mice were used to validate specificity of GIF-rtTA driver in chief cells. GIF-Cre-RnTnG mice were used to perform lineage tracing during homoeostasis and acute metaplasia development. L635 treatment was used to induce acute mucosal injury and coimmunofluorescence staining was performed for various gastric lineage markers.ResultsWe demonstrated that mature chief cells, rather than isthmal progenitor cells, serve as the predominant origin of SPEM cells during the metaplastic process after acute mucosal injury. Furthermore, we observed long-term label-retaining chief cells at 1 year after the GFP labelling in chief cells. However, only a very small subset of the long-term label-retaining chief cells displayed the reprogramming ability in homoeostasis. In contrast, we identified chief cell-originating SPEM cells as contributing to lineages within foveolar cell hyperplasia in response to the acute mucosal injury.ConclusionOur study provides pivotal evidence for cell plasticity and lineage contributions from differentiated gastric chief cells during acute metaplasia development.

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A signalling cascade of IL-33 to IL-13 regulates metaplasia in the mouse stomach

Gut ◽

10.1136/gutjnl-2016-312779 ◽

2017 ◽

Vol 67 (5) ◽

pp. 805-817 ◽

Cited By ~ 28

Author(s):

Christine P Petersen ◽

Anne R Meyer ◽

Carlo De Salvo ◽

Eunyoung Choi ◽

Cameron Schlegel ◽

...

Keyword(s):

Parietal Cell ◽

Cell Loss ◽

Wild Type ◽

Macrophage Population ◽

Alternatively Activated Macrophages ◽

Macrophage Polarisation ◽

Signalling Network ◽

Spasmolytic Polypeptide ◽

Signalling Cascade ◽

Alternatively Activated

ObjectiveAlternatively activated macrophages (M2) are associated with the progression of spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. However, the precise mechanism(s) and critical mediators that induce SPEM are unknown.DesignTo determine candidate genes important in these processes, macrophages from the stomach corpus of mice with SPEM (DMP-777-treated) or advanced SPEM (L635-treated) were isolated and RNA sequenced. Effects on metaplasia development after acute parietal cell loss induced by L635 were evaluated in interleukin (IL)-33, IL-33 receptor (ST2) and IL-13 knockout (KO) mice.ResultsProfiling of metaplasia-associated macrophages in the stomach identified an M2a-polarised macrophage population. Expression of IL-33 was significantly upregulated in macrophages associated with advanced SPEM. L635 induced metaplasia in the stomachs of wild-type mice, but not in the stomachs of IL-33 and ST2 KO mice. While IL-5 and IL-9 were not required for metaplasia induction, IL-13 KO mice did not develop metaplasia in response to L635. Administration of IL-13 to ST2 KO mice re-established the induction of metaplasia following acute parietal cell loss.ConclusionsMetaplasia induction and macrophage polarisation after parietal cell loss is coordinated through a cytokine signalling network of IL-33 and IL-13, linking a combined response to injury by both intrinsic mucosal mechanisms and infiltrating M2 macrophages.

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Altered metaplastic response ofwaved-2EGF receptor mutant mice to acute oxyntic atrophy

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00309.2005 ◽

2006 ◽

Vol 290 (4) ◽

pp. G793-G804 ◽

Cited By ~ 21

Author(s):

Masako Ogawa ◽

Sachiyo Nomura ◽

Andrea Varro ◽

Timothy C. Wang ◽

James R. Goldenring

Keyword(s):

Parietal Cell ◽

Egf Receptor ◽

Cell Loss ◽

Parietal Cells ◽

Receptor Ligands ◽

Gastric Metaplasia ◽

Spasmolytic Polypeptide ◽

Receptor Mutant ◽

Deficient Mice ◽

Rapid Emergence

Metaplastic cell lineages are putative precursors for the development of gastric adenocarcinoma. The loss of parietal cells (oxyntic atrophy) is the initiating step in the evolution of gastric fundic mucosal lineage changes including metaplasia and hyperplasia. However, the intrinsic mucosal factors that promote and modulate the emergence of metaplastic phenotypes remain obscure. Over the past several years, we have studied pharmacologically induced, reversible oxyntic atrophy in rodents treated with DMP-777, a drug that acts as a parietal cell secretory membrane protonophore. DMP-777 elicits a rapid loss of parietal cells followed by the emergence of foveolar hyperplasia and spasmolytic polypeptide (SP)-expressing metaplasia (SPEM). The objective of the present study was to provide further insights into the intrinsic mucosal factors regulating the emergence of SPEM in the setting of oxyntic atrophy. We therefore studied the effects of DMP-777 administration on both SP/trefoil factor (TFF)2-deficient mice, which lack SP/TFF2, a marker of SPEM, and waved-2 mice, which harbor a point mutation in the EGF receptor that attenuates its tyrosine kinase activity. As in wild-type mice, treatment with DMP-777 for 7 days did elicit SPEM in SP/TFF2-deficient mice. These results suggest that SP/TFF2 does not impact on the development of metaplasia after the induction of parietal cell loss. In contrast, waved-2 homozygous mice displayed accelerated SPEM development by 3 days of treatment with DMP-777. These findings indicate that attenuation of EGF receptor signaling in waved-2 mice does elicit a more rapid emergence of SPEM. The results support a role for EGF receptor ligands in the regulation of gastric metaplasia.

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Overexpression of Glycine-Extended Gastrin Inhibits Parietal Cell Loss and Atrophy in the Mouse Stomach

Cancer Research ◽

10.1158/0008-5472.can-04-0876 ◽

2004 ◽

Vol 64 (22) ◽

pp. 8160-8166 ◽

Cited By ~ 34

Author(s):

Guanglin Cui ◽

Theodore J. Koh ◽

Duan Chen ◽

Chun-Mei Zhao ◽

Shigeo Takaishi ◽

...

Keyword(s):

Parietal Cell ◽

Cell Loss

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994 – Mir-148A Regulates Chief Cell Plasticity in the Stomach

Gastroenterology ◽

10.1016/s0016-5085(19)37326-3 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-212

Author(s):

Yoojin Sohn ◽

Takahiro Shimizu ◽

Eunyoung Choi ◽

James R. Goldenring

Keyword(s):

Chief Cell ◽

Cell Plasticity

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LIN28B/let-7control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2000417117 ◽

2020 ◽

Vol 117 (36) ◽

pp. 22225-22236

Author(s):

Xiao-Jun Li ◽

Angelika Doetzlhofer

Keyword(s):

Hair Cell ◽

Hair Cells ◽

Rna Binding ◽

Mammalian Target Of Rapamycin ◽

Cell Loss ◽

Supporting Cell ◽

Dependent Manner ◽

Cell Plasticity ◽

Supporting Cells ◽

Cochlear Hair Cells

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNAlet-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

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The Role of Radiation Therapy in the Management of Catecholamine-Secreting Glomus Tumors

Otolaryngology ◽

10.1177/019459988809800209 ◽

1988 ◽

Vol 98 (2) ◽

pp. 150-154 ◽

Cited By ~ 17

Author(s):

Mitchell K. Schwaber ◽

Gerald S. Gussack ◽

Wanda Kirkpatrick

Keyword(s):

Radiation Therapy ◽

Skull Base ◽

Tumor Size ◽

Glomus Tumor ◽

Chief Cell ◽

Glomus Tumors ◽

Chief Cells ◽

Glomus Jugulare Tumor ◽

Radiation Cure

The major source of controversy that surrounds the use of radiation for glomus tumors is the finding of persistent chief cells years after completion of the treatment. Questions have been raised as to the viability of the irradiated chief cell and its capacity to proliferate. The radiotherapists consider a stable glomus tumor a radiation “cure,” whereas skull base surgeons are fearful that these lesions will continue to slowly grow and cause problems 20 to 30 years later. We have recently managed a patient who was not a candidate for surgery, with a catecholamine-secreting glomus jugulare tumor. after 4750 rad of radiation therapy, no changes in tumor size or in catecholamine secretion have been observed (at 20 months of followup). The implications of the case are discussed.

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