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Yang X, Zhang J, Ma J, Huang J, Wang P, Wang F, Tang X. Integrative investigation on the mechanisms of modified Zuojin pill (SQQT) in ameliorating gastric metaplasia. JOURNAL OF ETHNOPHARMACOLOGY 2025; 346:119643. [PMID: 40113112 DOI: 10.1016/j.jep.2025.119643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 03/08/2025] [Accepted: 03/15/2025] [Indexed: 03/22/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Zuojin pill is a well-known traditional Chinese medicine (TCM) for treating gastric disorders. The modified Zuojin pill (SQQT) has been used in the treatment of gastric metaplasia (GM) in China for decades. However, the mechanisms of SQQT treat GM remain unclear. AIM OF THE STUDY Our goals are to evaluate the effect of SQQT on GM and to investigate its potential mechanisms. METHODS An animal model of metaplasia was established to study the mechanism of SQQT. RNA-seq was employed to analyze the pathogenesis of GM. Network pharmacological approaches and molecular docking were used to elucidate the mechanisms of SQQT. Common targets of the SQQT and GM mechanism pathways are defined as the key mechanisms of SQQT's treatment in GM. The key mechanisms were validated through in vivo and in vitro experiments. RESULTS RNA-seq analysis of GM animals and network pharmacology of SQQT indicated that SQQT might treat GM via 20 pathways, including the PPAR pathway. Among the 3 core targets of the PPAR pathway, only PPARG is related to GM progression. Besides, the core components of SQQT have a lower affinity for binding to PPARG. The main mechanism of SQQT ameliorated GM is related to PPARG. In animal experiments, SQQT ameliorated GM through ROS decreasing, mitochondrial damage repairing, and protein marker rectification. In cell experiments, SQQT notably decreased the levels of ferroptosis and metaplasia markers including GPX4, PPARG, MUC6, and ACSL4. CONCLUSION SQQT ameliorated gastric metaplasia by inhibiting the PPARG/ferroptosis pathway.
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Affiliation(s)
- Xuefei Yang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China; Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Jiaqi Zhang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Jing Ma
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Jinke Huang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Ping Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Fengyun Wang
- Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
| | - Xudong Tang
- Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing, China; Institute of Digestive Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, China.
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Jeong H, Lee B, Cho SY, Lee Y, Kim J, Hur S, Cho K, Kim KH, Kim SH, Nam KT. Microbiota-derived short-chain fatty acids determine stem cell characteristics of gastric chief cells. Dev Cell 2025; 60:599-612.e6. [PMID: 39642880 DOI: 10.1016/j.devcel.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/07/2024] [Accepted: 11/08/2024] [Indexed: 12/09/2024]
Abstract
The gastric mucosa is a highly dynamic tissue that undergoes constant self-renewal through stem cell differentiation. Chief cells maintain a quiescent state in homeostasis but are responsible for regeneration after injury. Although the role of microbiome-host interactions in the intestine is well studied, less is known about these interactions in the stomach. Using the mouse organoid and germ-free mouse models, we show that microbiota-derived short-chain fatty acids (SCFAs) suppress the proliferation of chief cells in mice. This effect is mediated by activation of G-protein-coupled receptor 43. Most importantly, through metabolomics and transplantation studies, we show butyrate-producing Lactobacillus intestinalis modulates the proliferation of chief cells in mice. Our findings identify a mechanism by which the microbiota regulates the cell characteristics of chief cells, providing insight into the complex interplay between the host and its microbial environment and the mechanisms underlying gastric homeostasis, with potential therapeutic implications for gastric diseases.
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Affiliation(s)
- Haengdueng Jeong
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Buhyun Lee
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Soo Young Cho
- Department of Molecular and Life Science, Hanyang University, Ansan, Republic of Korea
| | - Yura Lee
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jiseon Kim
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sumin Hur
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Kyungrae Cho
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Kwang H Kim
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sung-Hee Kim
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Ki Taek Nam
- Department of Biomedical Science, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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Brown JW, Lin X, Nicolazzi GA, Liu X, Nguyen T, Radyk MD, Burclaff J, Mills JC. Cathartocytosis: Jettisoning of Unwanted Material during Cellular Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2024.06.11.598489. [PMID: 38915707 PMCID: PMC11195262 DOI: 10.1101/2024.06.11.598489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2024]
Abstract
Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins were not only digested during paligenosis but also excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was mechanistically independent of autophagy. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it "cathartocytosis". Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins would aid in downscaling and might also help bind and flush pathogens away from tissue.
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Wang H, Xu X, Ouyang Y, Fei X, He C, Yang X, Ren Y, Zhou Y, Chen S, Hu Y, Liu J, Ge Z, Wu WKK, Lu N, Xie C, Wu X, Zhu Y, Li N. The Protective Role of DDIT4 in Helicobacter pylori-induced Gastric Metaplasia Through Metabolic Regulation of Ferroptosis. Cell Mol Gastroenterol Hepatol 2024; 19:101448. [PMID: 39943905 PMCID: PMC11937681 DOI: 10.1016/j.jcmgh.2024.101448] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 03/17/2025]
Abstract
BACKGROUND & AIMS Helicobacter pylori (H pylori) infection is a significant factor leading to gastric atrophy, metaplasia and cancer development. Here, we investigated the role of the stress response gene DDIT4 in the pathogenesis of H pylori infection. METHODS Cell lines, transgenic mice, and human tissue samples were implemented. Proteomics were performed on Ddit4+/+ and Ddit4-/- mice infected with H pylori strain PMSS1. C57BL/6 mice were administered with tamoxifen to induce gastric metaplasia. Stomach tissues were analyzed for histopathologic features, reactive oxygen species, Fe2+, lipid peroxidation, expression of DDIT4, and ferroptosis-related proteins. RESULTS DDIT4 expression was upregulated at 6 hours but significantly decreased at 24 hours in response to H pylori infection in gastric epithelial cells. Gastric DDIT4 were downregulated in INS-GAS mice at 4 months post H pylori infection. Notably, H pylori infection led to more severe gastric metaplasia lesion in Ddit4-knockout mice. The proteomic profiling revealed an increase in ferroptosis in the gastric tissues of infected Ddit4-deficient mice, compared with infected wild-type mice. Mechanistically, knockout of DDIT4 promoted H pylori-induced ferroptosis through the accumulation of lipid peroxides and ROS levels, and alterations in proteins such as GPX4, ALOX15, and HMOX1. Overexpression of DDIT4 counteracted H pylori-induced stem cell marker CD44V9 through modulation of ferroptosis. Similarly, in another mouse model of gastric metaplasia treated with tamoxifen, as well as in human GIM tissues, we observed the loss of DDIT4 and induction of ferroptosis. CONCLUSIONS Our results indicate that DDIT4 serves as a protective factor against H pylori-induced gastric metaplasia by metabolic resistance to ferroptosis.
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Affiliation(s)
- Huan Wang
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Postdoctoral Innovation Practice Base, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xinbo Xu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yaobin Ouyang
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xiao Fei
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Cong He
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xianhe Yang
- Department of Science and Technology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yuping Ren
- Department of Rheumatology and Immunology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yanan Zhou
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Sihai Chen
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yi Hu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Jianping Liu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - William Ka Kei Wu
- Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
| | - Nonghua Lu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Chuan Xie
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Xidong Wu
- Department of Drug Safety Evaluation, Jiangxi Testing Center of Medical Instruments, Nanchang, China.
| | - Yin Zhu
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
| | - Nianshuang Li
- Department of Gastroenterology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China; Jiangxi Institute of Digestive Disease, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
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Henningfield CM, Kwang N, Tsourmas KI, Neumann J, Kawauchi S, Swarup V, MacGregor GR, Green KN. Generation of an inducible destabilized-domain Cre mouse line to target disease associated microglia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.09.18.613773. [PMID: 39345513 PMCID: PMC11429805 DOI: 10.1101/2024.09.18.613773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
The function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed a mouse strain that expresses destabilized-domain Cre recombinase (DD-Cre) from the Cst7 locus ( Cst7 DD-Cre ) and tested this in 5xFAD amyloidogenic, Ai14 tdTomato cre-reporter line mice. Dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in disease associated microglia (DAM) without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. This model should allow inducible cre-loxP targeting of DAMs, without leakiness. Highlights We developed a new mouse strain which specifically enables recombination of loxP sites in disease associated microglia (DAMs) and can be used to manipulate DAM-gene expression.DAMs represent a subset of plaque associated microglia (PAMs), and DAM expression increases with disease progression.Spatial transcriptomic analyses reveal that DAMs have higher expression of disease and inflammatory genes compared to other PAMs.
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Isakov V. Autoimmune gastritis studies and gastric cancer: True renaissance or bibliometric illusion. World J Gastroenterol 2024; 30:3783-3790. [PMID: 39221066 PMCID: PMC11362875 DOI: 10.3748/wjg.v30.i32.3783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 08/08/2024] [Accepted: 08/13/2024] [Indexed: 08/26/2024] Open
Abstract
A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.
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Affiliation(s)
- Vasily Isakov
- Department of Gastroenterology and Hepatology, Federal Research Center of Nutrition, Biotechnology and Food Safety, Moscow 115446, Russia
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Favret J, Nawaz MH, Patel M, Khaledi H, Gelb M, Shin D. Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice. Mol Ther 2024; 32:2207-2222. [PMID: 38734898 PMCID: PMC11286809 DOI: 10.1016/j.ymthe.2024.05.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 04/15/2024] [Accepted: 05/09/2024] [Indexed: 05/13/2024] Open
Abstract
Lysosomal galactosylceramidase (GALC) is expressed in all brain cells, including oligodendrocytes (OLs), microglia, and astrocytes, although the cell-specific function of GALC is largely unknown. Mutations in GALC cause Krabbe disease (KD), a fatal neurological lysosomal disorder that usually affects infants. To study how Galc ablation in each glial cell type contributes to Krabbe pathogenesis, we used conditional Galc-floxed mice. Here, we found that OL-specific Galc conditional knockout (CKO) in mice results in a phenotype that includes wasting, psychosine accumulation, and neuroinflammation. Microglia- or astrocyte-specific Galc deletion alone in mice did not show specific phenotypes. Interestingly, mice with CKO of Galc from both OLs and microglia have a more severe neuroinflammation with an increase in globoid cell accumulation than OL-specific CKO alone. Moreover, the enhanced phenotype occurred without additional accumulation of psychosine. Further studies revealed that Galc knockout (Galc-KO) microglia cocultured with Galc-KO OLs elicits globoid cell formation and the overexpression of osteopontin and monocyte chemoattractant protein-1, both proteins that are known to recruit immune cells and promote engulfment of debris and damaged cells. We conclude that OLs are the primary cells that initiate KD with an elevated psychosine level and microglia are required for the progression of neuroinflammation in a psychosine-independent manner.
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Affiliation(s)
- Jacob Favret
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA
| | - Mohammed Haseeb Nawaz
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA
| | - Mayuri Patel
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA
| | - Hamid Khaledi
- Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA
| | - Michael Gelb
- Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA 98195, USA
| | - Daesung Shin
- Department of Biotechnical and Clinical Laboratory Sciences, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA; Institute for Myelin and Glia Exploration, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA.
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Adkins-Threats M, Arimura S, Huang YZ, Divenko M, To S, Mao H, Zeng Y, Hwang JY, Burclaff JR, Jain S, Mills JC. Metabolic regulator ERRγ governs gastric stem cell differentiation into acid-secreting parietal cells. Cell Stem Cell 2024; 31:886-903.e8. [PMID: 38733994 PMCID: PMC11162331 DOI: 10.1016/j.stem.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 02/26/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024]
Abstract
Parietal cells (PCs) produce gastric acid to kill pathogens and aid digestion. Dysregulated PC census is common in disease, yet how PCs differentiate is unclear. Here, we identify the PC progenitors arising from isthmal stem cells, using mouse models and human gastric cells, and show that they preferentially express cell-metabolism regulator and orphan nuclear receptor Estrogen-related receptor gamma (Esrrg, encoding ERRγ). Esrrg expression facilitated the tracking of stepwise molecular, cellular, and ultrastructural stages of PC differentiation. EsrrgP2ACreERT2 lineage tracing revealed that Esrrg expression commits progenitors to differentiate into mature PCs. scRNA-seq indicated the earliest Esrrg+ PC progenitors preferentially express SMAD4 and SP1 transcriptional targets and the GTPases regulating acid-secretion signal transduction. As progenitors matured, ERRγ-dependent metabolic transcripts predominated. Organoid and mouse studies validated the requirement of ERRγ for PC differentiation. Our work chronicles stem cell differentiation along a single lineage in vivo and suggests ERRγ as a therapeutic target for PC-related disorders.
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Affiliation(s)
- Mahliyah Adkins-Threats
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Division of Biomedical and Biological Sciences, Washington University, St. Louis, MO 63130, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Sumimasa Arimura
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yang-Zhe Huang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Margarita Divenko
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah To
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Heather Mao
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jenie Y Hwang
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology and Laboratory Medicine, University of Texas Health San Antonio, San Antonio, TX 78249, USA
| | - Joseph R Burclaff
- Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Chapel Hill, NC 27599, USA
| | - Shilpa Jain
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Jason C Mills
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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Rhodes JD, Goldenring JR, Lee SH. Regulation of metaplasia and dysplasia in the stomach by the stromal microenvironment. Exp Mol Med 2024; 56:1322-1330. [PMID: 38825636 PMCID: PMC11263556 DOI: 10.1038/s12276-024-01240-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/03/2024] [Accepted: 03/03/2024] [Indexed: 06/04/2024] Open
Abstract
Research on the microenvironment associated with gastric carcinogenesis has focused on cancers of the stomach and often underestimates premalignant stages such as metaplasia and dysplasia. Since epithelial interactions with T cells, macrophages, and type 2 innate lymphoid cells (ILC2s) are indispensable for the formation of precancerous lesions in the stomach, understanding the cellular interactions that promote gastric precancer warrants further investigation. Although various types of immune cells have been shown to play important roles in gastric carcinogenesis, it remains unclear how stromal cells such as fibroblasts influence epithelial transformation in the stomach, especially during precancerous stages. Fibroblasts exist as distinct populations across tissues and perform different functions depending on the expression patterns of cell surface markers and secreted factors. In this review, we provide an overview of known microenvironmental components in the stroma with an emphasis on fibroblast subpopulations and their roles during carcinogenesis in tissues including breast, pancreas, and stomach. Additionally, we offer insights into potential targets of tumor-promoting fibroblasts and identify open areas of research related to fibroblast plasticity and the modulation of gastric carcinogenesis.
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Affiliation(s)
- Jared D Rhodes
- Program in Cancer Biology, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - James R Goldenring
- Program in Cancer Biology, Nashville, TN, USA.
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Nashville, TN, USA.
- Nashville VA Medical Center, Nashville, TN, USA.
| | - Su-Hyung Lee
- Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Section of Surgical Sciences, Nashville, TN, USA.
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Miao ZF, Sun JX, Huang XZ, Bai S, Pang MJ, Li JY, Chen HY, Tong QY, Ye SY, Wang XY, Hu XH, Li JY, Zou JW, Xu W, Yang JH, Lu X, Mills JC, Wang ZN. Metaplastic regeneration in the mouse stomach requires a reactive oxygen species pathway. Dev Cell 2024; 59:1175-1191.e7. [PMID: 38521055 DOI: 10.1016/j.devcel.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 10/07/2023] [Accepted: 03/04/2024] [Indexed: 03/25/2024]
Abstract
In pyloric metaplasia, mature gastric chief cells reprogram via an evolutionarily conserved process termed paligenosis to re-enter the cell cycle and become spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Here, we use single-cell RNA sequencing (scRNA-seq) following injury to the murine stomach to analyze mechanisms governing paligenosis at high resolution. Injury causes induced reactive oxygen species (ROS) with coordinated changes in mitochondrial activity and cellular metabolism, requiring the transcriptional mitochondrial regulator Ppargc1a (Pgc1α) and ROS regulator Nf2el2 (Nrf2). Loss of the ROS and mitochondrial control in Ppargc1a-/- mice causes the death of paligenotic cells through ferroptosis. Blocking the cystine transporter SLC7A11(xCT), which is critical in lipid radical detoxification through glutathione peroxidase 4 (GPX4), also increases ferroptosis. Finally, we show that PGC1α-mediated ROS and mitochondrial changes also underlie the paligenosis of pancreatic acinar cells. Altogether, the results detail how metabolic and mitochondrial changes are necessary for injury response, regeneration, and metaplasia in the stomach.
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Affiliation(s)
- Zhi-Feng Miao
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China.
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Shi Bai
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Min-Jiao Pang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jia-Yi Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Han-Yu Chen
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Qi-Yue Tong
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Shi-Yu Ye
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xin-Yu Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xiao-Hai Hu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jing-Ying Li
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jin-Wei Zou
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Wen Xu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jun-Hao Yang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Xi Lu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China
| | - Jason C Mills
- Section of Gastroenterology & Hepatology, Department of Medicine, Departments of Pathology & Immunology, Molecular and Cellular Biology, Baylor College of Medicine, 535E Anderson-Jones Building, One Baylor Plaza, Houston, TX, USA.
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, 155 N Nanjing Street, Shenyang, Liaoning, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China; Institute of Health Sciences, China Medical University, No.77 Puhe Road, Shenyang, Liaoning, China.
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11
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Klochkova A, Karami AL, Fuller AD, Parham LR, Panchani SR, Natarajan S, Jackson JL, Mu A, Tan Y, Cai KQ, Klein-Szanto AJ, Muir AB, Tétreault MP, Graña X, Hamilton KE, Whelan KA. Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential. Cell Mol Gastroenterol Hepatol 2024; 18:15-40. [PMID: 38452871 PMCID: PMC11126828 DOI: 10.1016/j.jcmgh.2024.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 02/27/2024] [Accepted: 02/28/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND & AIMS Autophagy plays roles in esophageal pathologies both benign and malignant. Here, we aim to define the role of autophagy in esophageal epithelial homeostasis. METHODS We generated tamoxifen-inducible, squamous epithelial-specific Atg7 (autophagy related 7) conditional knockout mice to evaluate effects on esophageal homeostasis and response to the carcinogen 4-nitroquinoline 1-oxide (4NQO) using histologic and biochemical analyses. We fluorescence-activated cell sorted esophageal basal cells based on fluorescence of the autophagic vesicle (AV)-identifying dye Cyto-ID and then subjected these cells to transmission electron microscopy, image flow cytometry, three-dimensional organoid assays, RNA sequencing, and cell cycle analysis. Three-dimensional organoids were subjected to passaging, single-cell RNA sequencing, cell cycle analysis, and immunostaining. RESULTS Genetic autophagy inhibition in squamous epithelium resulted in increased proliferation of esophageal basal cells under homeostatic conditions and also was associated with significant weight loss in mice treated with 4NQO that further displayed perturbed epithelial tissue architecture. Esophageal basal cells with high AV level (Cyto-IDHigh) displayed limited organoid formation capability on initial plating but passaged more efficiently than their counterparts with low AV level (Cyto-IDLow). RNA sequencing suggested increased autophagy in Cyto-IDHigh esophageal basal cells along with decreased cell cycle progression, the latter of which was confirmed by cell cycle analysis. Single-cell RNA sequencing of three-dimensional organoids generated by Cyto-IDLow and Cyto-IDHigh cells identified expansion of 3 cell populations and enrichment of G2/M-associated genes in the Cyto-IDHigh group. Ki67 expression was also increased in organoids generated by Cyto-IDHigh cells, including in basal cells localized beyond the outermost cell layer. CONCLUSIONS Autophagy contributes to maintenance of the esophageal proliferation-differentiation gradient. Esophageal basal cells with high AV level exhibit limited proliferation and generate three-dimensional organoids with enhanced self-renewal capacity.
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Affiliation(s)
- Alena Klochkova
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Adam L Karami
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Annie D Fuller
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Louis R Parham
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Surali R Panchani
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Shruthi Natarajan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Jazmyne L Jackson
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Anbin Mu
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Yinfei Tan
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Kathy Q Cai
- Histopathology Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | - Amanda B Muir
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Marie-Pier Tétreault
- Department of Medicine, Gastroenterology and Hepatology Division, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Xavier Graña
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania
| | - Kathryn E Hamilton
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Kelly A Whelan
- Fels Cancer Institute for Personalized Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania; Department of Cancer & Cellular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, Pennsylvania.
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12
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Wu Y, Adeniyi-Ipadeola G, Adkins-Threats M, Seasock M, Suarez-Reyes C, Fujiwara R, Bottazzi ME, Song L, Mills JC, Weatherhead JE. Host gastric corpus microenvironment facilitates Ascaris suum larval hatching and infection in a murine model. PLoS Negl Trop Dis 2024; 18:e0011930. [PMID: 38324590 PMCID: PMC10878500 DOI: 10.1371/journal.pntd.0011930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 02/20/2024] [Accepted: 01/21/2024] [Indexed: 02/09/2024] Open
Abstract
Ascariasis (roundworm) is the most common parasitic helminth infection globally and can lead to significant morbidity in children including chronic lung disease. Children become infected with Ascaris spp. via oral ingestion of eggs. It has long been assumed that Ascaris egg hatching and larval translocation across the gastrointestinal mucosa to initiate infection occurs in the small intestine. Here, we show that A. suum larvae hatched in the host stomach in a murine model. Larvae utilize acidic mammalian chitinase (AMCase; acid chitinase; Chia) from chief cells and acid pumped by parietal cells to emerge from eggs on the surface of gastric epithelium. Furthermore, antagonizing AMCase and gastric acid in the stomach decreases parasitic burden in the liver and lungs and attenuates lung disease. Given Ascaris eggs are chitin-coated, the gastric corpus would logically be the most likely organ for egg hatching, though this is the first study directly evincing the essential role of the host gastric corpus microenvironment. These findings point towards potential novel mechanisms for therapeutic targets to prevent ascariasis and identify a new biomedical significance of AMCase in mammals.
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Affiliation(s)
- Yifan Wu
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Grace Adeniyi-Ipadeola
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Mahliyah Adkins-Threats
- Department of Medicine, Section of Gastroenterology, Baylor College of Medicine, Houston, Texas, United States of America
- Departments of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Matthew Seasock
- Department of Medicine, Immunology, Pathology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Charlie Suarez-Reyes
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Ricardo Fujiwara
- Departamento de Parasitologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Maria Elena Bottazzi
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Lizhen Song
- Department of Medicine, Immunology, Pathology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jason C. Mills
- Department of Medicine, Section of Gastroenterology, Baylor College of Medicine, Houston, Texas, United States of America
- Departments of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jill E. Weatherhead
- Department of Pediatrics, Division of Pediatric Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, Texas, United States of America
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13
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Hong X, Li H, Lin Y, Luo L, Xu W, Kang J, Li J, Huang B, Xu Y, Pan H, Guo S. Efficacy and potential therapeutic mechanism of Weiwei decoction on Spasmolytic polypeptide-expressing metaplasia in Helicobacter pylori-infected and Atp4a-knockout mice. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117062. [PMID: 37598768 DOI: 10.1016/j.jep.2023.117062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/16/2023] [Accepted: 08/17/2023] [Indexed: 08/22/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spasmolytic polypeptide-expressing metaplasia (SPEM) is characterized by mucus cell morphologies at the base of gastric glands, which is considered advanced SPEM when accompanied with an increase in transcripts associated with intestinal-type gastric cancer. Weiwei decoction (WWD) was modified from "Si-Jun-Zi Tang," which has been used for thousands of years in China against gastric atrophy and metaplasia. AIM OF THE STUDY To investigate the effects and potential mechanisms of WWD against advanced SPEM. MATERIALS AND METHODS Liquid chromatography-mass spectrometry was employed to analyze the constituents of WWD. Five-month-infected Helicobacter pylori (H. pylori) Sydney strain 1 C57BL/6J mice and 6-week-old ATPase H+/K+ transporting subunit alpha-knockout mice (Atp4a-/-) were given folic acid (1.95 mg/kg) or WWD (13.65 g/kg, 27.30 g/kg, 54.60 g/kg) by gavage for one month. RESULTS WWD demonstrated beneficial effects on gastric mucosal pathology and mucus secretion. In H. pylori-infected mice, WWD effectively reduced the expression of GSII and inhibited the mRNA levels of key markers associated with advanced SPEM, including Clu, Cftr, Wfdc2, Dmbt1, and Gpx2. Similarly, in Atp4a-/- mice, WWD significantly decreased the expressions of GSII and Clusterin, and inhibited the mRNA levels of Wfdc2, Cftr, Dmbt1, and Gpx2. Notably, WWD restored the expression of markers for chief cells (PGC, GIF) and parietal cells (ATP4A), particularly in the medium- and high-dose groups, indicating its potential anti-atrophy effect on H. pylori-infected and Atp4a-/- mice. WWD administration resulted in a decline in TFF2 expression to baseline levels, suggesting that the mucous protection mediated by TFF2 was unaffected. Furthermore, the infiltration of CD163+F4/80+ M2 macrophages in the gastric mucosa of H. pylori-infected mice was reduced after WWD treatment, indicating a potential modulatory role of WWD on M2 macrophages. CONCLUSION WWD exerted protective effects against SPEM in H. pylori-infected and Atp4a-/- mice. The optimal doses of WWD were found to be medium doses in H. pylori-infected mice and high doses in Atp4a-/- mice. These effects include inhibition of transcripts associated with intestinal-type gastric adenocarcinoma, restoration of ATP4A and PGC expression, and reduction of M2 macrophage infiltration. These findings provide valuable insights into the therapeutic effects of WWD on advanced SPEM and highlight its potential as a treatment option.
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Affiliation(s)
- Xinxin Hong
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Haiwen Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Yandan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Liuru Luo
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Weijun Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Jianyuan Kang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Jingwei Li
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Bin Huang
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Yifei Xu
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China
| | - Huafeng Pan
- Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Shaoju Guo
- Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, 518033, China.
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14
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Privitera G, Williams JJ, De Salvo C. The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer. Cancers (Basel) 2024; 16:522. [PMID: 38339273 PMCID: PMC10854712 DOI: 10.3390/cancers16030522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/19/2024] [Accepted: 01/23/2024] [Indexed: 02/12/2024] Open
Abstract
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
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Affiliation(s)
- Giuseppe Privitera
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20142 Milan, Italy
| | - Joseph J. Williams
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
| | - Carlo De Salvo
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; (G.P.); (J.J.W.)
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15
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Xiong M, Chen X, Wang H, Tang X, Wang Q, Li X, Ma H, Ye X. Combining transcriptomics and network pharmacology to reveal the mechanism of Zuojin capsule improving spasmolytic polypeptide-expressing metaplasia. JOURNAL OF ETHNOPHARMACOLOGY 2024; 318:117075. [PMID: 37625606 DOI: 10.1016/j.jep.2023.117075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/12/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Spasmolytic polypeptide-expressing metaplasia (SPEM) is a gastric precancerous lesion (GPL). Zuojin capsule (ZJC), consisting of Coptis chinensis Franch. (Ranunculaceae, recorded in the Chinese Pharmacopoeia as Rhizoma Coptidis) and Tetradium ruticarpum (A.Juss.) T.G.Hartley (Rutaceae, recorded in the Chinese Pharmacopoeia as Fructus Evodiae), has long been used for various gastrointestinal diseases. However, the effect and mechanism of ZJC on SPEM remain unclear. AIM OF THE STUDY To clarify the role of ZJC in improving SPEM and study its mechanism. MATERIALS AND METHODS The study utilized SPEM mice induced by 250 mg/kg body weight of tamoxifen (TAM) to assess the effects of ZJC and investigate its possible mechanisms. A strategy of transcriptomics combined with network pharmacology was conducted to explore the targets and mechanisms of ZJC in improving SPEM. The "ingredients-target-pathway" network was constructed, and the possible connections were verified by RT-qPCR and Western blot assays. RESULTS ZJC significantly attenuated the abnormal serological indices, destruction of the gastric mucosal structure, hyperplasia of gastric pits, increased gastric mucus, massive secretion of CD44 and TFF2, oxyntic atrophy and massive proliferation of stem/progenitor cells in TAM-induced SPEM mice. Combined transcriptomics and network pharmacology analysis, 50 core targets of ZJC related to SPEM improvement were obtained. KEGG results showed that the core targets were significantly enriched in the cell cycle, and PI3K-AKT signaling pathway. The top-ranked targets according to PPI network analysis were CDK1, CCNB1, and CCNA2, which are also associated with cell cycle. Combined experiments demonstrated that ZJC can induce G2/M phase cycle arrest and inhibit TAM-induced malignant proliferation by regulating abnormal activation of cell cycle-related proteins such as CDK1, CCNB1, CCNA2 and PI3K-AKT signaling pathways. CONCLUSIONS ZJC may improve TAM-induced SPEM by inhibiting abnormal activation of cell cycle-related proteins (CDK1, CCNB1, CCNA2) and PI3K-AKT signaling pathway. This finding supports the use of ZJC, a famous traditional Chinese medicine compound, as a potential treatment for gastric precancerous lesions.
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Affiliation(s)
- Mengyuan Xiong
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiantao Chen
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Hongmei Wang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiang Tang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Qiaojiao Wang
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
| | - Xuegang Li
- College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Hang Ma
- College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.
| | - Xiaoli Ye
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
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16
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Ahlback A, Gentek R. Fate-Mapping Macrophages: From Ontogeny to Functions. Methods Mol Biol 2024; 2713:11-43. [PMID: 37639113 DOI: 10.1007/978-1-0716-3437-0_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
Macrophages are vital to the physiological function of most tissues, but also contribute to disease through a multitude of pathological roles. They are thus highly plastic and heterogeneous. It is now well recognized that macrophages develop from several distinct progenitors from embryogenesis onwards and extending throughout life. Tissue-resident macrophages largely originate from embryonic sources and in many cases self-maintain independently without monocyte input. However, in certain tissues, monocyte-derived macrophages replace these over time or as a result of tissue injury and inflammation. This additional layer of heterogeneity has introduced many questions regarding the influence of origin on fate and function of macrophages in health and disease. To comprehensively address these questions, appropriate methods of tracing macrophage ontogeny are required. This chapter explores why ontogeny is of vital importance in macrophage biology and how to delineate macrophage populations by origin through genetic fate mapping. First, we summarize the current view of macrophage ontogeny and briefly discuss how origin may influence macrophage function in homeostasis and pathology. We go on to make the case for genetic fate mapping as the gold standard and briefly review different fate-mapping models. We then put forward our recommendations for fate-mapping strategies best suited to answer specific research questions and finally discuss the strengths and limitations of currently available models.
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Affiliation(s)
- Anna Ahlback
- The University of Edinburgh, Institute for Regeneration and Repair, Centre for Reproductive Health & Centre for Inflammation Research, Edinburgh, UK
| | - Rebecca Gentek
- The University of Edinburgh, Institute for Regeneration and Repair, Centre for Reproductive Health & Centre for Inflammation Research, Edinburgh, UK.
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17
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LaFleur MW, Lemmen AM, Streeter ISL, Nguyen TH, Milling LE, Derosia NM, Hoffman ZM, Gillis JE, Tjokrosurjo Q, Markson SC, Huang AY, Anekal PV, Montero Llopis P, Haining WN, Doench JG, Sharpe AH. X-CHIME enables combinatorial, inducible, lineage-specific and sequential knockout of genes in the immune system. Nat Immunol 2024; 25:178-188. [PMID: 38012416 PMCID: PMC10881062 DOI: 10.1038/s41590-023-01689-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/20/2023] [Indexed: 11/29/2023]
Abstract
Annotation of immunologic gene function in vivo typically requires the generation of knockout mice, which is time consuming and low throughput. We previously developed CHimeric IMmune Editing (CHIME), a CRISPR-Cas9 bone marrow delivery system for constitutive, ubiquitous deletion of single genes. Here we describe X-CHIME, four new CHIME-based systems for modular and rapid interrogation of gene function combinatorially (C-CHIME), inducibly (I-CHIME), lineage-specifically (L-CHIME) or sequentially (S-CHIME). We use C-CHIME and S-CHIME to assess the consequences of combined deletion of Ptpn1 and Ptpn2, an embryonic lethal gene pair, in adult mice. We find that constitutive deletion of both PTPN1 and PTPN2 leads to bone marrow hypoplasia and lethality, while inducible deletion after immune development leads to enteritis and lethality. These findings demonstrate that X-CHIME can be used for rapid mechanistic evaluation of genes in distinct in vivo contexts and that PTPN1 and PTPN2 have some functional redundancy important for viability in adult mice.
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Affiliation(s)
- Martin W LaFleur
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ashlyn M Lemmen
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Ivy S L Streeter
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Thao H Nguyen
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lauren E Milling
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nicole M Derosia
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Zachary M Hoffman
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jacob E Gillis
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Qin Tjokrosurjo
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Samuel C Markson
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Amy Y Huang
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | - John G Doench
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
- Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
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18
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Loe AKH, Rao-Bhatia A, Wei Z, Kim JE, Guan B, Qin Y, Hong M, Kwak HS, Liu X, Zhang L, Wrana JL, Guo H, Kim TH. YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration. Cell Rep 2023; 42:113497. [PMID: 38041813 DOI: 10.1016/j.celrep.2023.113497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 06/25/2023] [Accepted: 11/09/2023] [Indexed: 12/04/2023] Open
Abstract
Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.
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Affiliation(s)
- Adrian K H Loe
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Abilasha Rao-Bhatia
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Zhao Wei
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan 250012, Shandong, China; Shandong Engineering Research Center of Biomarker and Artificial Intelligence Application, Jinan, China
| | - Jung-Eun Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Bingxin Guan
- Department of Pathology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China
| | - Yan Qin
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Minji Hong
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Hyo Sang Kwak
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Xiaoyu Liu
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China
| | - Leyi Zhang
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Jeffrey L Wrana
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - Haiyang Guo
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, Shandong, China; Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, Shandong, China; Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, Shandong, China.
| | - Tae-Hee Kim
- Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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19
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Edelmuth RCL, Riascos MC, Al Asadi H, Greenberg JA, Miranda IC, Najah H, Crawford CV, Schnoll-Sussman FH, Finnerty BM, Fahey TJ, Zarnegar R. Gastric development of pancreatic acinar cell metaplasia after Vonoprazan therapy in rats. Surg Endosc 2023; 37:9366-9372. [PMID: 37644156 DOI: 10.1007/s00464-023-10371-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 07/30/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND Vonoprazan is a new acid-suppressing drug that received FDA approval in 2022. It reversibly inhibits gastric acid secretion by competing with the potassium ions on the luminal surface of the parietal cells (potassium-competitive acid blockers or P-CABs). Vonoprazan has been on the market for a short time and there are many clinical trials to support its clinical application. However, medical experience and comprehensive clinical data is still limited, especially on how and if, gastric histology is altered due to therapy. METHODS A 12-week experiment trial with 30 Wistar rats was to assess the presence of gastrointestinal morphologic abnormalities upon administration of omeprazole and vonoprazan. At six weeks of age, rats were randomly assigned to one of 5 groups: (1) saline as negative control group, (2) oral omeprazole (40 mg/kg), as positive control group, (3) oral omeprazole (40 mg/kg) for 4 weeks, proceeded by 8 weeks off omeprazole, (4) oral vonoprazan (4 mg/kg), as positive control group, and (5) oral vonoprazan (4 mg/kg) for 4 weeks, proceeded by 8 weeks off vonoprazan. RESULTS We identified non-inflammatory alterations characterized by parietal (oxyntic) cell loss and chief (zymogen) cell hyperplasia and replacement by pancreatic acinar cell metaplasia (PACM). No significant abnormalities were identified in any other tissues in the hepatobiliary and gastrointestinal tracts. CONCLUSION PACM has been reported in gastric mucosa, at the esophagogastric junction, at the distal esophagus, and in Barrett esophagus. However, the pathogenesis of this entity is still unclear. Whereas some authors have suggested that PACM is an acquired process others have raised the possibility of PACM being congenital in nature. Our results suggest that the duration of vonoprazan administration at a dose of 4 mg/kg plays an important role in the development of PACM.
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Affiliation(s)
- Rodrigo C L Edelmuth
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Maria Cristina Riascos
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Hala Al Asadi
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Jacques A Greenberg
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Ileana C Miranda
- Laboratory of Comparative Pathology, Weill Cornell Medical College, New York-Presbyterian Hospital, Memorial Sloan Kettering Cancer Center, The Rockefeller University, New York, NY, USA
| | - Haythem Najah
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Carl V Crawford
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
| | - Felice H Schnoll-Sussman
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
| | - Brendan M Finnerty
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Thomas J Fahey
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA
| | - Rasa Zarnegar
- Department of Surgery, Division of Endocrine & Minimally Invasive Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, 525 East 68Th Street, K-836, New York, NY, 10065, USA.
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20
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Meinzinger A, Zsigmond Á, Horváth P, Kellenberger A, Paréj K, Tallone T, Flachner B, Cserhalmi M, Lőrincz Z, Cseh S, Shmerling D. RuX: A Novel, Flexible, and Sensitive Mifepristone-Induced Transcriptional Regulation System. Int J Cell Biol 2023; 2023:7121512. [PMID: 37941807 PMCID: PMC10630016 DOI: 10.1155/2023/7121512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 09/26/2023] [Accepted: 10/03/2023] [Indexed: 11/10/2023] Open
Abstract
Inducible gene regulation methods are indispensable in diverse biological applications, yet many of them have severe limitations in their applicability. These include inducer toxicity, a limited variety of organisms the given system can be used in, and side effects of the induction method. In this study, a novel inducible system, the RuX system, was created using a mutant ligand-binding domain of the glucocorticoid receptor (CS1/CD), used together with various genetic elements such as the Gal4 DNA-binding domain or Cre recombinase. The RuX system is shown to be capable of over 1000-fold inducibility, has flexible applications, and is offered for use in cell cultures.
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Affiliation(s)
| | | | | | | | | | - Tiziano Tallone
- Department of Endocrinology, Metabolism and Cardiovascular Research, University of Fribourg, Fribourg, Switzerland
| | | | | | | | - Sándor Cseh
- TargetEx Biosciences Ltd., Dunakeszi, Hungary
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21
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O'Keefe RN, Carli ALE, Baloyan D, Chisanga D, Shi W, Afshar-Sterle S, Eissmann MF, Poh AR, Pal B, Seillet C, Locksley RM, Ernst M, Buchert M. A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development. Nat Commun 2023; 14:6872. [PMID: 37898600 PMCID: PMC10613282 DOI: 10.1038/s41467-023-42215-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 10/04/2023] [Indexed: 10/30/2023] Open
Abstract
Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.
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Affiliation(s)
- Ryan N O'Keefe
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Annalisa L E Carli
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - David Baloyan
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - David Chisanga
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Wei Shi
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Shoukat Afshar-Sterle
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Bhupinder Pal
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Cyril Seillet
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Richard M Locksley
- Department of Medicine, University of California San Francisco, San Francisco, USA
- Howard Hughes Medical Institute, University of California San Francisco, San Francisco, USA
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute, Heidelberg, Australia.
- School of Cancer Medicine, La Trobe University, Bundoora, Australia.
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22
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Kim DH, Wang Y, Jung H, Field RL, Zhang X, Liu TC, Ma C, Fraser JS, Brestoff JR, Van Dyken SJ. A type 2 immune circuit in the stomach controls mammalian adaptation to dietary chitin. Science 2023; 381:1092-1098. [PMID: 37676935 PMCID: PMC10865997 DOI: 10.1126/science.add5649] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 08/08/2023] [Indexed: 09/09/2023]
Abstract
Dietary fiber improves metabolic health, but host-encoded mechanisms for digesting fibrous polysaccharides are unclear. In this work, we describe a mammalian adaptation to dietary chitin that is coordinated by gastric innate immune activation and acidic mammalian chitinase (AMCase). Chitin consumption causes gastric distension and cytokine production by stomach tuft cells and group 2 innate lymphoid cells (ILC2s) in mice, which drives the expansion of AMCase-expressing zymogenic chief cells that facilitate chitin digestion. Although chitin influences gut microbial composition, ILC2-mediated tissue adaptation and gastrointestinal responses are preserved in germ-free mice. In the absence of AMCase, sustained chitin intake leads to heightened basal type 2 immunity, reduced adiposity, and resistance to obesity. These data define an endogenous metabolic circuit that enables nutrient extraction from an insoluble dietary constituent by enhancing digestive function.
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Affiliation(s)
- Do-Hyun Kim
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yilin Wang
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Haerin Jung
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Rachael L. Field
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Xinya Zhang
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Ta-Chiang Liu
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Changqing Ma
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - James S. Fraser
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA
| | - Jonathan R. Brestoff
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Steven J. Van Dyken
- Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, USA
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23
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Steiner AJ, Zheng Y, Tang Y. Characterization of a rhabdomyosarcoma reveals a critical role for SMG7 in cancer cell viability and tumor growth. Sci Rep 2023; 13:10152. [PMID: 37349371 PMCID: PMC10287741 DOI: 10.1038/s41598-023-36568-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 06/06/2023] [Indexed: 06/24/2023] Open
Abstract
Soft-tissue sarcomas (STSs) are a rare and diverse group of mesenchymal cancers plagued with aggression, poor response to systemic therapy, and high rates of recurrence. Although STSs generally have low mutational burdens, the most commonly mutated genes are tumor suppressors, which frequently acquire mutations inducing nonsense-mediated mRNA decay (NMD). This suggests that STS cells may exploit NMD to suppress these anti-cancer genes. To examine the role that the NMD factor SMG7 plays in STS, we developed an inducible knockout mouse model in the Trp53-/- background. Here, we isolated a subcutaneous STS and identified it as a rhabdomyosarcoma (RMS). We report that knockout of SMG7 significantly inhibited NMD in our RMS cells, which led to the induction of NMD targets GADD45b and the tumor suppressor GAS5. The loss of NMD and upregulation of these anti-cancer genes were concomitant with the loss of RMS cell viability and inhibited tumor growth. Importantly, SMG7 was dispensable for homeostasis in our mouse embryonic fibroblasts and adult mice. Overall, our data show that the loss of SMG7 induces a strong anti-cancer effect both in vitro and in vivo. We present here the first evidence that disrupting SMG7 function may be tolerable and provide a therapeutic benefit for STS treatment.
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Affiliation(s)
- Alexander J Steiner
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Yang Zheng
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA
| | - Yi Tang
- Department of Regenerative and Cancer Cell Biology, Albany Medical College, 47 New Scotland Avenue, Albany, NY, 12208, USA.
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24
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Kim J, Lee C, Han J, Jeong H, Wang S, Choi YH, Jung Y. Targeted Deletion of Thymosin Beta 4 in Hepatic Stellate Cells Ameliorates Liver Fibrosis in a Transgenic Mouse Model. Cells 2023; 12:1658. [PMID: 37371128 DOI: 10.3390/cells12121658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/06/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Liver fibrosis is the most common feature of liver disease, and activated hepatic stellate cells (HSCs) are the main contributors to liver fibrosis. Thus, finding key targets that modulate HSC activation is important to prevent liver fibrosis. Previously, we showed that thymosin β4 (Tβ4) influenced HSC activation by interacting with the Hedgehog pathway in vitro. Herein, we generated Tβ4 conditional knockout (Tβ4-flox) mice to investigate in vivo functions of Tβ4 in liver fibrosis. To selectively delete Tβ4 in activated HSCs, double-transgenic (DTG) mice were generated by mating Tβ4-flox mice with α-smooth muscle actin (α-Sma)-Cre-ERT2 mice, and these mice were administered carbon tetrachloride (CCl4) or underwent bile duct ligation to induce liver fibrosis. Tβ4 was selectively suppressed in the activated HSCs of DTG mouse liver, and this reduction attenuated liver injury, including fibrosis, in both fibrotic models by repressing Hedgehog (Hh) signaling. In addition, the re-expression of Tβ4 by an adeno-associated virus reversed the effect of HSC-specific Tβ4 deletion and led to liver fibrosis with Hh activation in CCl4-exposed mice treated with tamoxifen. In conclusion, our results demonstrate that Tβ4 is a crucial regulator of HSC activation, suggesting it as a novel therapeutic target for curing liver fibrosis.
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Affiliation(s)
- Jieun Kim
- Institute of System Biology, Pusan National University, Pusan 46241, Republic of Korea
- Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
| | - Chanbin Lee
- Institute of System Biology, Pusan National University, Pusan 46241, Republic of Korea
- Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
| | - Jinsol Han
- Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
| | - Hayeong Jeong
- Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
| | - Sihyung Wang
- New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, Dong-Eui University College of Korean Medicine, Pusan 47227, Republic of Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
- Department of Biological Sciences, College of Natural Sciences, Pusan National University, Pusan 46241, Republic of Korea
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25
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Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
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Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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Willet SG, Thanintorn N, McNeill H, Huh SH, Ornitz DM, Huh WJ, Hoft SG, DiPaolo RJ, Mills JC. SOX9 Governs Gastric Mucous Neck Cell Identity and Is Required for Injury-Induced Metaplasia. Cell Mol Gastroenterol Hepatol 2023; 16:325-339. [PMID: 37270061 PMCID: PMC10444955 DOI: 10.1016/j.jcmgh.2023.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
BACKGROUND & AIMS Acute and chronic gastric injury induces alterations in differentiation within the corpus of the stomach called pyloric metaplasia. Pyloric metaplasia is characterized by the death of parietal cells and reprogramming of mitotically quiescent zymogenic chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Overall, pyloric metaplastic units show increased proliferation and specific expansion of mucous lineages, both by proliferation of normal mucous neck cells and recruitment of SPEM cells. Here, we identify Sox9 as a potential gene of interest in the regulation of mucous neck and SPEM cell identity in the stomach. METHODS We used immunostaining and electron microscopy to characterize the expression pattern of SRY-box transcription factor 9 (SOX9) during murine gastric development, homeostasis, and injury in homeostasis, after genetic deletion of Sox9 and after targeted genetic misexpression of Sox9 in the gastric epithelium and chief cells. RESULTS SOX9 is expressed in all early gastric progenitors and strongly expressed in mature mucous neck cells with minor expression in the other principal gastric lineages during adult homeostasis. After injury, strong SOX9 expression was induced in the neck and base of corpus units in SPEM cells. Adult corpus units derived from Sox9-deficient gastric progenitors lacked normal mucous neck cells. Misexpression of Sox9 during postnatal development and adult homeostasis expanded mucous gene expression throughout corpus units including within the chief cell zone in the base. Sox9 deletion specifically in chief cells blunts their reprogramming into SPEM. CONCLUSIONS Sox9 is a master regulator of mucous neck cell differentiation during gastric development. Sox9 also is required for chief cells to fully reprogram into SPEM after injury.
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Affiliation(s)
- Spencer G Willet
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri.
| | - Nattapon Thanintorn
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Helen McNeill
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Sung-Ho Huh
- Department of Otolaryngology-Head and Neck Surgery, University of Mississippi Medical Center, Jackson, Mississippi
| | - David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri
| | - Won Jae Huh
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut
| | - Stella G Hoft
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Richard J DiPaolo
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri
| | - Jason C Mills
- Section of Gastroenterology, Department of Medicine, Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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Kumagai K, Shimizu T, Nikaido M, Hirano T, Kakiuchi N, Takeuchi Y, Minamiguchi S, Sakurai T, Teramura M, Utsumi T, Hiramatsu Y, Nakanishi Y, Takai A, Miyamoto S, Ogawa S, Seno H. On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma. J Pathol 2023; 259:362-368. [PMID: 36625379 DOI: 10.1002/path.6050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 12/01/2022] [Accepted: 01/05/2023] [Indexed: 01/11/2023]
Abstract
Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Ken Kumagai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Mitsuhiro Nikaido
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomonori Hirano
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Nobuyuki Kakiuchi
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuhide Takeuchi
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.,Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.,Clinical Bio Resource Center, Kyoto University Hospital, Kyoto, Japan
| | | | - Takaki Sakurai
- Department of Diagnostic Pathology, Kansai Electric Power Hospital, Osaka, Japan
| | - Mari Teramura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Takahiro Utsumi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Shin'ichi Miyamoto
- Department of Gastroenterology and Hepatology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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28
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Samovski D, Jacome-Sosa M, Abumrad NA. Fatty Acid Transport and Signaling: Mechanisms and Physiological Implications. Annu Rev Physiol 2023; 85:317-337. [PMID: 36347219 DOI: 10.1146/annurev-physiol-032122-030352] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Long-chain fatty acids (FAs) are components of plasma membranes and an efficient fuel source and also serve as metabolic regulators through FA signaling mediated by membrane FA receptors. Impaired tissue FA uptake has been linked to major complications of obesity, including insulin resistance, cardiovascular disease, and type 2 diabetes. Fatty acid interactions with a membrane receptor and the initiation of signaling can modify pathways related to nutrient uptake and processing, cell proliferation or differentiation, and secretion of bioactive factors. Here, we review the major membrane receptors involved in FA uptake and FA signaling. We focus on two types of membrane receptors for long-chain FAs: CD36 and the G protein-coupled FA receptors FFAR1 and FFAR4. We describe key signaling pathways and metabolic outcomes for CD36, FFAR1, and FFAR4 and highlight the parallels that provide insight into FA regulation of cell function.
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Affiliation(s)
- Dmitri Samovski
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Miriam Jacome-Sosa
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA;
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA; .,Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA
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29
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Matsuo J, Chuang LSH, Tong JJL, Douchi D, Ito Y. Identifying Adult Stomach Tissue Stem/Progenitor Cells Using the Iqgap3-2A-CreERT2 Mouse. Methods Mol Biol 2023; 2691:3-17. [PMID: 37355533 DOI: 10.1007/978-1-0716-3331-1_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/26/2023]
Abstract
Identification of unique gene markers of normal and cancer stem cells is an effective strategy to study cells of origin and understand tumor behavior. Lineage tracing experiments using the Cre recombinase driven by a stem cell-specific promoter in the CreERT2 reporter mouse model enables identification of adult stem cells and delineation of stem cell activities in vivo. In our recent research on the mouse stomach, Iqgap3 was identified as a homeostatic stem cell marker located in the isthmus of the stomach epithelium. Lineage tracing with the Iqgap3-2A-CreERT2;Rosa26-LSL-tdTomato mouse model demonstrated stem cell activity in Iqgap3-expressing cells. Using the Iqgap3-2A-CreERT2 mouse model to target oncogenic KrasG12D expression to Iqgap3-expressing cells, we observed the rapid development of precancerous metaplasia in the stomach and proposed that aberrant Iqgap3-expressing cells may be critical determinants of early carcinogenesis. In this chapter, we detail a lineage tracing protocol to assess stem cell activity in the murine stomach. We also describe the procedure of inducing KrasG12D expression in Iqgap3-expressing homeostatic stem cells to explore their role as cells of origin and to trace the early cellular changes that precede neoplastic transformation.
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Affiliation(s)
- Junichi Matsuo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Linda Shyue Huey Chuang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jasmine Jie Lin Tong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Daisuke Douchi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai City, Japan
| | - Yoshiaki Ito
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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30
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Orzechowska-Licari EJ, LaComb JF, Giarrizzo M, Yang VW, Bialkowska AB. Intestinal Epithelial Regeneration in Response to Ionizing Irradiation. J Vis Exp 2022:10.3791/64028. [PMID: 35969101 PMCID: PMC9631267 DOI: 10.3791/64028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/29/2023] Open
Abstract
The intestinal epithelium consists of a single layer of cells yet contains multiple types of terminally differentiated cells, which are generated by the active proliferation of intestinal stem cells located at the bottom of intestinal crypts. However, during events of acute intestinal injury, these active intestinal stem cells undergo cell death. Gamma irradiation is a widely used colorectal cancer treatment, which, while therapeutically efficacious, has the side effect of depleting the active stem cell pool. Indeed, patients frequently experience gastrointestinal radiation syndrome while undergoing radiotherapy, in part due to active stem cell depletion. The loss of active intestinal stem cells in intestinal crypts activates a pool of typically quiescent reserve intestinal stem cells and induces dedifferentiation of secretory and enterocyte precursor cells. If not for these cells, the intestinal epithelium would lack the ability to recover from radiotherapy and other such major tissue insults. New advances in lineage-tracing technologies allow tracking of the activation, differentiation, and migration of cells during regeneration and have been successfully employed for studying this in the gut. This study aims to depict a method for the analysis of cells within the mouse intestinal epithelium following radiation injury.
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Affiliation(s)
| | - Joseph F LaComb
- Department of Medicine, Renaissance School of Medicine at Stony Brook University
| | - Michael Giarrizzo
- Department of Medicine, Renaissance School of Medicine at Stony Brook University
| | - Vincent W Yang
- Department of Medicine, Renaissance School of Medicine at Stony Brook University; Department of Physiology and Biophysics, Renaissance School of Medicine at Stony Brook University
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31
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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32
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Rapid establishment of murine gastrointestinal organoids using mechanical isolation method. Biochem Biophys Res Commun 2022; 608:30-38. [DOI: 10.1016/j.bbrc.2022.03.151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 11/22/2022]
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33
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Yang H, Zhou X, Hu B. The 'reversibility' of chronic atrophic gastritis after the eradication of Helicobacter pylori. Postgrad Med 2022; 134:474-479. [PMID: 35382697 DOI: 10.1080/00325481.2022.2063604] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gram-negative bacterium Helicobacter pylori (H. pylori) infection is lifelong and usually acquired in childhood, which is etiologically linked to gastric cancer (GC). H. pylori gastritis is defined as an infectious disease with varying severity in virtually all infected subjects. Chronic atrophic gastritis (CAG) is the precancerous condition with the decrease or the loss of gastric glands, which can further be replaced by metaplasia or fibrosis. Patients with advanced stages of CAG are at higher risk of GC and should be followed up with a high-quality endoscopy every 3 years. H. pylori infection is the most common cause and its eradication is recommended, which may contribute to the regression of CAG. However, it is controversial whether CAG is reversible after eradication therapy. In the review, we discuss recent studies which provide important insights into whether CAG is 'reversibility' and when it may progress into GC after eradicating H. pylori.
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Affiliation(s)
- Hang Yang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xinyue Zhou
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bing Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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34
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Xu Y, Schrank PR, Williams JW. Macrophage Fate Mapping. Curr Protoc 2022; 2:e456. [PMID: 35687806 PMCID: PMC9328150 DOI: 10.1002/cpz1.456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tissue-resident macrophages are present in all tissues where they perform homeostatic and immune surveillance functions. In many tissues, resident macrophages develop from embryonic progenitors, which mature into a self-maintaining population through local proliferation. However, tissue-resident macrophages can be supported by recruited monocyte-derived macrophages during scenarios such as tissue growth, infection, or sterile inflammation. Circulating blood monocytes arise from hematopoietic stem cell progenitors and possess unique gene profiles that support additional functions within the tissue. Determining cell origins (ontogeny) and cellular turnover within tissues has become important to understanding monocyte and macrophage contributions to tissue homeostasis and disease. Fate mapping, or lineage tracing, is a promising approach to tracking cells based on unique gene expression driving reporter systems, often downstream of a Cre-recombinase-mediated excision event, to express a fluorescent protein. This approach is typically deployed temporally with developmental stage, disease onset, or in association with key stages of inflammation resolution. Importantly, myeloid fate mapping can be combined with many emerging technologies, including single-cell RNA-sequencing and spatial imaging. The application of myeloid cell fate mapping approaches has allowed for impactful discoveries regarding myeloid ontogeny, tissue residency, and monocyte fate within disease models. This protocol outline will discuss a variety of myeloid fate mapping approaches, including constitutive and inducible labeling approaches in adult and embryo tissues. This article outlines basic approaches and models used in mice for fate mapping macrophages. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Adult Fate Mapping Basic Protocol 2: Embryonic Fate Mapping.
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Affiliation(s)
- Yingzheng Xu
- Center for Immunology Department of Integrative Biology & Physiology University of Minnesota Minneapolis Minnesota
| | - Patricia R. Schrank
- Center for Immunology Department of Integrative Biology & Physiology University of Minnesota Minneapolis Minnesota
| | - Jesse W. Williams
- Center for Immunology Department of Integrative Biology & Physiology University of Minnesota Minneapolis Minnesota
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35
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Lee JH, Kim S, Han S, Min J, Caldwell B, Bamford AD, Rocha ASB, Park J, Lee S, Wu SHS, Lee H, Fink J, Pilat-Carotta S, Kim J, Josserand M, Szep-Bakonyi R, An Y, Ju YS, Philpott A, Simons BD, Stange DE, Choi E, Koo BK, Kim JK. p57 Kip2 imposes the reserve stem cell state of gastric chief cells. Cell Stem Cell 2022; 29:826-839.e9. [PMID: 35523142 PMCID: PMC9097776 DOI: 10.1016/j.stem.2022.04.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 02/17/2022] [Accepted: 04/01/2022] [Indexed: 11/19/2022]
Abstract
Adult stem cells constantly react to local changes to ensure tissue homeostasis. In the main body of the stomach, chief cells produce digestive enzymes; however, upon injury, they undergo rapid proliferation for prompt tissue regeneration. Here, we identified p57Kip2 (p57) as a molecular switch for the reserve stem cell state of chief cells in mice. During homeostasis, p57 is constantly expressed in chief cells but rapidly diminishes after injury, followed by robust proliferation. Both single-cell RNA sequencing and dox-induced lineage tracing confirmed the sequential loss of p57 and activation of proliferation within the chief cell lineage. In corpus organoids, p57 overexpression induced a long-term reserve stem cell state, accompanied by altered niche requirements and a mature chief cell/secretory phenotype. Following the constitutive expression of p57 in vivo, chief cells showed an impaired injury response. Thus, p57 is a gatekeeper that imposes the reserve stem cell state of chief cells in homeostasis.
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Affiliation(s)
- Ji-Hyun Lee
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Somi Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Department of New Biology, DGIST, Daegu 42988, Republic of Korea
| | - Seungmin Han
- Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK
| | - Jimin Min
- Department of Surgery and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Brianna Caldwell
- Department of Surgery and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Aileen-Diane Bamford
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Andreia Sofia Batista Rocha
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - JinYoung Park
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Sieun Lee
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Szu-Hsien Sam Wu
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Heetak Lee
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Juergen Fink
- Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Sandra Pilat-Carotta
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Jihoon Kim
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria; Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon, Gyeonggi-do, Republic of Korea
| | - Manon Josserand
- Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK
| | - Réka Szep-Bakonyi
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria
| | - Yohan An
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Young Seok Ju
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Anna Philpott
- Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Department of Oncology, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Benjamin D Simons
- Wellcome Trust/Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK; Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Wilberforce Road, Cambridge CB3 0WA, UK
| | - Daniel E Stange
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany
| | - Eunyoung Choi
- Department of Surgery and Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
| | - Bon-Kyoung Koo
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Dr. Bohr-Gasse 3, Vienna, 1030, Austria; Center for Genome Engineering, Institute for Basic Science, 55, Expo-ro, Yuseong-gu, Daejeon 34126, Republic of Korea.
| | - Jong Kyoung Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang 37673, Republic of Korea; Department of New Biology, DGIST, Daegu 42988, Republic of Korea.
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36
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Bhave S, Ho WLN, Cheng K, Omer M, Bousquet N, Guyer RA, Hotta R, Goldstein AM. Tamoxifen administration alters gastrointestinal motility in mice. Neurogastroenterol Motil 2022; 34:e14357. [PMID: 35279902 DOI: 10.1111/nmo.14357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 12/13/2021] [Accepted: 01/28/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tamoxifen is widely used for Cre-estrogen receptor-mediated genomic recombination in transgenic mouse models to mark cells for lineage tracing and to study gene function. However, recent studies have highlighted off-target effects of tamoxifen in various tissues and cell types when used for induction of Cre recombination. Despite the widespread use of these transgenic Cre models to assess gastrointestinal (GI) function, the effect of tamoxifen exposure on GI motility has not been described. METHODS We examined the effects of tamoxifen on GI motility by measuring total GI transit, gastric emptying, small intestinal transit, and colonic contractility in wild-type adult mice. KEY RESULTS We observed a significant delay in total GI transit in tamoxifen-treated mice, with unaltered gastric emptying, accelerated small intestinal transit, and abnormal colonic motility. CONCLUSION Our findings highlight the importance of considering GI motility alterations induced by tamoxifen when designing protocols that utilize tamoxifen as a Cre-driver for studying GI function.
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Affiliation(s)
- Sukhada Bhave
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wing Lam N Ho
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Katarina Cheng
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Meredith Omer
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nicole Bousquet
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Richard A Guyer
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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37
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Liabeuf D, Oshima M, Stange DE, Sigal M. Stem Cells, Helicobacter pylori, and Mutational Landscape: Utility of Preclinical Models to Understand Carcinogenesis and to Direct Management of Gastric Cancer. Gastroenterology 2022; 162:1067-1087. [PMID: 34942172 DOI: 10.1053/j.gastro.2021.12.252] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 12/20/2022]
Abstract
Several genetic and environmental factors increase gastric cancer (GC) risk, with Helicobacter pylori being the main environmental agent. GC is thought to emerge through a sequence of morphological changes that have been elucidated on the molecular level. New technologies have shed light onto pathways that are altered in GC, involving mutational and epigenetic changes and altered signaling pathways. Using various new model systems and innovative approaches, the relevance of such alterations for the emergence and progression of GC has been validated. Here, we highlight the key strategies and the resulting achievements. A major step is the characterization of epithelial stem cell behavior in the healthy stomach. These data, obtained through new reporter mouse lines and lineage tracing, enabled insights into the processes that control cellular proliferation, self-renewal, and differentiation of gastric stem cells. It has become evident that these cells and pathways are often deregulated in carcinogenesis. Second, insights into how H pylori colonizes gastric glands, directly interacts with stem cells, and alters cellular and genomic integrity, as well as the characterization of tissue responses to infection, provide a comprehensive picture of how this bacterium contributes to gastric carcinogenesis. Third, the development of stem cell- and tissue-specific reporter mice have driven our understanding of the signals and mutations that promote different types of GC and now also enable the study of more advanced, metastasized stages. Finally, organoids from human tissue have allowed insights into gastric carcinogenesis by validating mutational and signaling alterations in human primary cells and opening a route to predicting responses to personalized treatment.
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Affiliation(s)
- Dylan Liabeuf
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Daniel E Stange
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany, German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Michael Sigal
- Department of Internal Medicine, Division of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Germany; Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
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Dacheux MA, Lee SC, Shin Y, Norman DD, Lin KH, E S, Yue J, Benyó Z, Tigyi GJ. Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells. Cancers (Basel) 2022; 14:cancers14061586. [PMID: 35326737 PMCID: PMC8946623 DOI: 10.3390/cancers14061586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/07/2022] [Accepted: 03/17/2022] [Indexed: 01/27/2023] Open
Abstract
Although metastases are the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasizes to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knock out the ATX gene in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/loxP system (Sftpc-CreERT2/Enpp2fl/fl) to generate conditional knockout (KO) mice in which ATX is specifically deleted in ATII cells (i.e., Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allowed us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% (unpaired t-test, p = 0.028) compared to Sftpc-WT control mice, suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p < 0.0001) and TNFα (unpaired t-test, p = 0.0003), which could favor the increase in infiltrating CD8+ T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis.
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Affiliation(s)
- Mélanie A. Dacheux
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Sue Chin Lee
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Yoojin Shin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Derek D. Norman
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Kuan-Hung Lin
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
| | - Shuyu E
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (S.E.); (J.Y.)
| | - Junming Yue
- Department of Pathology and Laboratory Medicine, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (S.E.); (J.Y.)
| | - Zoltán Benyó
- Institute of Translational Medicine, Semmelweis University, H-1428 Budapest, Hungary;
| | - Gábor J. Tigyi
- Department of Physiology, College of Medicine, University of Tennessee Health Science Center (UTHSC), Memphis, TN 38163, USA; (M.A.D.); (S.C.L.); (Y.S.); (D.D.N.); (K.-H.L.)
- Correspondence: ; Tel.: +1-901-448-4793
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Sáenz JB, Vargas N, Cho CJ, Mills JC. Regulation of the double-stranded RNA response through ADAR1 licenses metaplastic reprogramming in gastric epithelium. JCI Insight 2022; 7:153511. [PMID: 35132959 PMCID: PMC8855806 DOI: 10.1172/jci.insight.153511] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 12/15/2021] [Indexed: 01/17/2023] Open
Abstract
Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.
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Affiliation(s)
- José B Sáenz
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Nancy Vargas
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine.,Department of Pathology and Immunology; and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
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Goldenring JR, Mills JC. Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond. Gastroenterology 2022; 162:415-430. [PMID: 34728185 PMCID: PMC8792220 DOI: 10.1053/j.gastro.2021.10.036] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 02/03/2023]
Abstract
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
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Affiliation(s)
- James R Goldenring
- Nashville Veterans Affairs Medical Center, Vanderbilt University School of Medicine, Nashville, Tennessee; Section of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Department of Medicine, Baylor College of Medicine, Houston, Texas; Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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Douchi D, Yamamura A, Matsuo J, Melissa Lim YH, Nuttonmanit N, Shimura M, Suda K, Chen S, Pang S, Kohu K, Abe T, Shioi G, Kim G, Shabbir A, Srivastava S, Unno M, Bok-Yan So J, Teh M, Yeoh KG, Chuang LSH, Ito Y. Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus. Gastroenterology 2021; 161:1907-1923.e26. [PMID: 34391772 DOI: 10.1053/j.gastro.2021.08.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 07/17/2021] [Accepted: 08/09/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND & AIMS Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model. METHODS We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice. RESULTS Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC transcript-expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma. CONCLUSIONS The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.
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Affiliation(s)
- Daisuke Douchi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akihiro Yamamura
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Junichi Matsuo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Yi Hui Melissa Lim
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Napat Nuttonmanit
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Mitsuhiro Shimura
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuto Suda
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Sabirah Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - ShuChin Pang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Kazuyoshi Kohu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Takaya Abe
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Go Shioi
- Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
| | - Guowei Kim
- Department of Surgery, National University Health System, National University of Singapore, Singapore
| | - Asim Shabbir
- Department of Surgery, National University Health System, National University of Singapore, Singapore
| | | | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Jimmy Bok-Yan So
- Department of Surgery, National University Health System, National University of Singapore, Singapore
| | - Ming Teh
- Department of Pathology, National University of Singapore, Singapore
| | - Khay Guan Yeoh
- Department of Medicine, National University of Singapore, Singapore
| | | | - Yoshiaki Ito
- Cancer Science Institute of Singapore, National University of Singapore, Singapore.
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Chen WQ, Tian FL, Zhang JW, Yang XJ, Li YP. Preventive and inhibitive effects of Yiwei Xiaoyu granules on the development and progression of spasmolytic polypeptide-expressing metaplasia lesions. World J Gastrointest Oncol 2021; 13:1741-1754. [PMID: 34853647 PMCID: PMC8603444 DOI: 10.4251/wjgo.v13.i11.1741] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/10/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Spasmolytic polypeptide-expressing metaplasia (SPEM) is a potential preneoplastic lesion.
AIM To elucidate the microRNA (miR)-7-mediated preventive and inhibitive effects of Yiwei Xiaoyu granules (YWXY) in SPEM lesions.
METHODS Gastric mucosa biopsies were collected from chronic atrophic gastritis patients and healthy people with signed informed consent. YWXY was administered to the mice with induced SPEM by tamoxifen, and the gastric mucosa was harvested on the tenth day of the experiment. Then immunohistochemistry and immunofluorescence were performed to validate the SPEM, lesions and the potential mechanism was investigated. RNA transcripts were detected with reverse transcription-quantitative polymerase chain reaction.
RESULTS The expression of miR-7 was downregulated in the SPEM lesions, and expression of trefoil factor 2 (TFF2) and clusterin was high in the human gastric mucosa. In vivo experiments showed that YWXY could inhibit the cell proliferation in the tamoxifen-induced SPEM lesions by regulating Ki67. Simultaneously, YWXY could restore the expression of miR-7 by regulating TFF2 by detection with immunofluorescence but not with reverse transcription-quantitative polymerase chain reaction, indicating its potential mechanism of targeting miR-7 by mediating TFF2. The expression of vascular endothelial growth factor-β and gastric intrinsic factor was restored within 3 d of YWXY administration for the SPEM lesions, speculating that the possible mechanism of YWXY is to inhibit the development and progression of SPEM by regulating vascular endothelial growth factor-β and gastric intrinsic factor.
CONCLUSION miR-7 downregulation is an early event in SPEM through regulation of TFF2 in human gastric mucosa. YWXY is able to inhibit the cell proliferation and restore the expression of miR-7 by mediating TFF2 in the SPEM mouse model.
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Affiliation(s)
- Wan-Qun Chen
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Feng-Liang Tian
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Jin-Wei Zhang
- Department of Dermatology and Cosmetology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Xiao-Jun Yang
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Yan-Ping Li
- Department of Gastroenterology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
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Jacome-Sosa M, Miao ZF, Peche VS, Morris EF, Narendran R, Pietka KM, Samovski D, Lo HYG, Pietka T, Varro A, Love-Gregory L, Goldenring JR, Kuda O, Gamazon ER, Mills JC, Abumrad NA. CD36 maintains the gastric mucosa and associates with gastric disease. Commun Biol 2021; 4:1247. [PMID: 34728772 PMCID: PMC8563937 DOI: 10.1038/s42003-021-02765-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 10/06/2021] [Indexed: 12/19/2022] Open
Abstract
The gastric epithelium is often exposed to injurious elements and failure of appropriate healing predisposes to ulcers, hemorrhage, and ultimately cancer. We examined the gastric function of CD36, a protein linked to disease and homeostasis. We used the tamoxifen model of gastric injury in mice null for Cd36 (Cd36-/-), with Cd36 deletion in parietal cells (PC-Cd36-/-) or in endothelial cells (EC-Cd36-/-). CD36 expresses on corpus ECs, on PC basolateral membranes, and in gastrin and ghrelin cells. Stomachs of Cd36-/- mice have altered gland organization and secretion, more fibronectin, and inflammation. Tissue respiration and mitochondrial efficiency are reduced. Phospholipids increased and triglycerides decreased. Mucosal repair after injury is impaired in Cd36-/- and EC-Cd36-/-, not in PC-Cd36-/- mice, and is due to defect of progenitor differentiation to PCs, not of progenitor proliferation or mature PC dysfunction. Relevance to humans is explored in the Vanderbilt BioVu using PrediXcan that links genetically-determined gene expression to clinical phenotypes, which associates low CD36 mRNA with gastritis, gastric ulcer, and gastro-intestinal hemorrhage. A CD36 variant predicted to disrupt an enhancer site associates (p < 10-17) to death from gastro-intestinal hemorrhage in the UK Biobank. The findings support role of CD36 in gastric tissue repair, and its deletion associated with chronic diseases that can predispose to malignancy.
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Affiliation(s)
- Miriam Jacome-Sosa
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
| | - Zhi-Feng Miao
- Department of Surgical Oncology, Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, First Hospital of China Medical University, Shenyang, China
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Vivek S Peche
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Edward F Morris
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Ramkumar Narendran
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Kathryn M Pietka
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Dmitri Samovski
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Hei-Yong G Lo
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Terri Pietka
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrea Varro
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Latisha Love-Gregory
- Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - James R Goldenring
- Departments of Surgery and Cell and Developmental Biology, Vanderbilt University Medical Center and VA Medical Center, Nashville, TN, USA
| | - Ondrej Kuda
- Institute of Physiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic
| | - Eric R Gamazon
- Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Jason C Mills
- Gastroenterology & Hepatology Section, Departments of Medicine and of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
| | - Nada A Abumrad
- Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
- Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
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Hagen SJ. Mucosal defense: gastroduodenal injury and repair mechanisms. Curr Opin Gastroenterol 2021; 37:609-614. [PMID: 34475337 PMCID: PMC8511296 DOI: 10.1097/mog.0000000000000775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW The mucosal barrier serves as a primary interface between the environment and host. In daily life, superficial injury to the gastric or duodenal mucosa occurs regularly but heals rapidly by a process called 'restitution'. Persistent injury to the gastroduodenal mucosa also occurs but initiates a regenerative lesion with specific wound healing mechanisms that attempt to repair barrier function. If not healed, these lesions can be the site of neoplasia development in a chronic inflammatory setting. This review summarizes the past year of advances in understanding mucosal repair in the gastroduodenal mucosa, which occurs as a defense mechanism against injury. RECENT FINDINGS Organoids are an emerging new tool that allows for the correlation of in vivo and in vitro models; organoids represent an important reductionist model to probe specific aspects of injury and repair mechanisms that are limited to epithelial cells. Additionally, proof-of-concept studies show that machine learning algorithms may ultimately assist with identifying novel, targetable pathways to pursue in therapeutic interventions. Gut-on-chip technology and single cell RNA-sequencing contributed to new understanding of gastroduodenal regenerative lesions after injury by identifying networks and interactions that are involved in the repair process. SUMMARY Recent updates provide new possibilities for identifying novel molecular targets for the treatment of acute and superficial mucosal injury, mucosal regeneration, and regenerative lesions in the gastrointestinal tract.
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Affiliation(s)
- Susan J. Hagen
- Department of Surgery
- Beth Israel Deaconess Medical Center
- Harvard Medical School, Boston, MA 02215
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45
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Matsuo J, Douchi D, Myint K, Mon NN, Yamamura A, Kohu K, Heng DL, Chen S, Mawan NA, Nuttonmanit N, Li Y, Srivastava S, Ho SWT, Lee NYS, Lee HK, Adachi M, Tamura A, Chen J, Yang H, Teh M, So JBY, Yong WP, Tan P, Yeoh KG, Chuang LSH, Tsukita S, Ito Y. Iqgap3-Ras axis drives stem cell proliferation in the stomach corpus during homoeostasis and repair. Gut 2021; 70:1833-1846. [PMID: 33293280 PMCID: PMC8458072 DOI: 10.1136/gutjnl-2020-322779] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 11/13/2020] [Accepted: 11/14/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Tissue stem cells are central regulators of organ homoeostasis. We looked for a protein that is exclusively expressed and functionally involved in stem cell activity in rapidly proliferating isthmus stem cells in the stomach corpus. DESIGN We uncovered the specific expression of Iqgap3 in proliferating isthmus stem cells through immunofluorescence and in situ hybridisation. We performed lineage tracing and transcriptomic analysis of Iqgap3 +isthmus stem cells with the Iqgap3-2A-tdTomato mouse model. Depletion of Iqgap3 revealed its functional importance in maintenance and proliferation of stem cells. We further studied Iqgap3 expression and the associated gene expression changes during tissue repair after tamoxifen-induced damage. Immunohistochemistry revealed elevated expression of Iqgap3 in proliferating regions of gastric tumours from patient samples. RESULTS Iqgap3 is a highly specific marker of proliferating isthmus stem cells during homoeostasis. Iqgap3+isthmus stem cells give rise to major cell types of the corpus unit. Iqgap3 expression is essential for the maintenance of stem potential. The Ras pathway is a critical partner of Iqgap3 in promoting strong proliferation in isthmus stem cells. The robust induction of Iqgap3 expression following tissue damage indicates an active role for Iqgap3 in tissue regeneration. CONCLUSION IQGAP3 is a major regulator of stomach epithelial tissue homoeostasis and repair. The upregulation of IQGAP3 in gastric cancer suggests that IQGAP3 plays an important role in cancer cell proliferation.
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Affiliation(s)
- Junichi Matsuo
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Daisuke Douchi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Khine Myint
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Naing Naing Mon
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Akihiro Yamamura
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuyoshi Kohu
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Dede Liana Heng
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Sabirah Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Nur Astiana Mawan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Napat Nuttonmanit
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Ying Li
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Shamaine Wei Ting Ho
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
| | - Nicole Yee Shin Lee
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
| | - Hong Kai Lee
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
| | - Makoto Adachi
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Atsushi Tamura
- Department of Pharmacology, School of Medicine, Teikyo University, Tokyo, Japan,Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan,Laboratory of Barriology and Cell Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Jinmiao Chen
- Singapore Immunology Network, Agency for Science, Technology and Research, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Ming Teh
- Department of Pathology, National University of Singapore, Singapore
| | - Jimmy Bok-Yan So
- Department of Surgery, National University Health System, National University of Singapore, Singapore
| | - Wei Peng Yong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Department of Hematology-Oncology, National University Cancer Institute, Singapore
| | - Patrick Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore,Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore,Genome Institute of Singapore, Singapore
| | - Khay Guan Yeoh
- Department of Medicine, National University of Singapore, Singapore,Department of Gastroenterology and Hepatology, National University Hospital, Singapore
| | | | - Sachiko Tsukita
- Strategic Innovation and Research Center, Teikyo University, Tokyo, Japan .,Laboratory of Barriology and Cell Biology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Yoshiaki Ito
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
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46
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Wyatt KD, Sakamoto K, Watford WT. Tamoxifen administration induces histopathologic changes within the lungs of Cre-recombinase-negative mice: A case report. Lab Anim 2021; 56:297-303. [PMID: 34551640 DOI: 10.1177/00236772211042968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Tamoxifen is commonly used as a cancer treatment in humans and for inducing genetic alterations using Cre-lox mouse models in the research setting. However, the extent of tamoxifen off-target effects in animal research is underappreciated. Here, we report significant changes in cellular infiltration in Cre-recombinase-negative mice treated with tamoxifen intraperitoneally. These changes were noted in the lungs, which were characterized by the presence of alveolitis, vasculitis, and pleuritis. Despite significant immunological changes in response to tamoxifen treatment, clinical symptoms were not observed. This study provides a cautionary note that tamoxifen treatment alone leads to histologic alterations that may obscure research interpretations and further highlights the need for the development of alternative mouse models for inducible Cre-mediated deletion.
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Affiliation(s)
- Kara D Wyatt
- Department of Infectious Diseases, University of Georgia, USA
| | | | - Wendy T Watford
- Department of Infectious Diseases, University of Georgia, USA
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47
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Radyk MD, Spatz LB, Peña BL, Brown JW, Burclaff J, Cho CJ, Kefalov Y, Shih C, Fitzpatrick JAJ, Mills JC. ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program. EMBO Rep 2021; 22:e51806. [PMID: 34309175 PMCID: PMC8419698 DOI: 10.15252/embr.202051806] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 06/04/2021] [Accepted: 06/18/2021] [Indexed: 12/20/2022] Open
Abstract
Differentiated cells across multiple species and organs can re-enter the cell cycle to aid in injury-induced tissue regeneration by a cellular program called paligenosis. Here, we show that activating transcription factor 3 (ATF3) is induced early during paligenosis in multiple cellular contexts, transcriptionally activating the lysosomal trafficking gene Rab7b. ATF3 and RAB7B are upregulated in gastric and pancreatic digestive-enzyme-secreting cells at the onset of paligenosis Stage 1, when cells massively induce autophagic and lysosomal machinery to dismantle differentiated cell morphological features. Their expression later ebbs before cells enter mitosis during Stage 3. Atf3-/- mice fail to induce RAB7-positive autophagic and lysosomal vesicles, eventually causing increased death of cells en route to Stage 3. Finally, we observe that ATF3 is expressed in human gastric metaplasia and during paligenotic injury across multiple other organs and species. Thus, our findings indicate ATF3 is an evolutionarily conserved gene orchestrating the early paligenotic autodegradative events that must occur before cells are poised to proliferate and contribute to tissue repair.
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Affiliation(s)
- Megan D Radyk
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Lillian B Spatz
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Bianca L Peña
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Jeffrey W Brown
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Joseph Burclaff
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Charles J Cho
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Yan Kefalov
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
| | - Chien‐Cheng Shih
- Washington University Center for Cellular ImagingWashington University School of MedicineSt. LouisMOUSA
| | - James AJ Fitzpatrick
- Washington University Center for Cellular ImagingWashington University School of MedicineSt. LouisMOUSA
- Departments of Neuroscience and Cell Biology & PhysiologyWashington University School of MedicineSt. LouisMOUSA
- Department of Biomedical EngineeringWashington University in St. LouisSt. LouisMOUSA
| | - Jason C Mills
- Division of GastroenterologyDepartment of MedicineWashington University School of MedicineSt. LouisMOUSA
- Department of Developmental BiologyWashington University School of MedicineSt. LouisMOUSA
- Department of Pathology and ImmunologyWashington University School of MedicineSt. LouisMOUSA
- Present address:
Section of Gastroenterology and HepatologyDepartments of Medicine and PathologyBaylor College of MedicineHoustonTXUSA
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48
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Jeong H, Lee B, Kim KH, Cho SY, Cho Y, Park J, Lee Y, Oh Y, Hwang BR, Jang AR, Park JH, Park JH, Jeong SH, Lee D, Lee YC, Lim KM, Goldenring JR, Nam KT. WFDC2 Promotes Spasmolytic Polypeptide-Expressing Metaplasia Through the Up-Regulation of IL33 in Response to Injury. Gastroenterology 2021; 161:953-967.e15. [PMID: 34116028 PMCID: PMC8380710 DOI: 10.1053/j.gastro.2021.05.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 05/27/2021] [Accepted: 05/29/2021] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS WAP 4-disulfide core domain protein 2 (WFDC2), also known as human epididymis protein 4, is a small secretory protein that is highly expressed in fibrosis and human cancers, particularly in the ovaries, lungs, and stomach. However, the role of WFDC2 in carcinogenesis is not fully understood. The present study aimed to investigate the role of WFDC2 in gastric carcinogenesis with the use of preneoplastic metaplasia models. METHODS Three spasmolytic polypeptide-expressing metaplasia (SPEM) models were established in both wild-type and Wfdc2-knockout mice with DMP-777, L635, and high-dose tamoxifen, respectively. To reveal the functional role of WFDC2, we performed transcriptomic analysis with DMP-777-treated gastric corpus specimens. RESULTS Wfdc2-knockout mice exhibited remarkable resistance against oxyntic atrophy, SPEM emergence, and accumulation of M2-type macrophages in all 3 SPEM models. Transcriptomic analysis revealed that Wfdc2-knockout prevented the up-regulation of interleukin-33 (IL33) expression in the injured mucosal region of SPEM models. Notably, supplementation of recombinant WFDC2 induced IL33 production and M2 macrophage polarization, and ultimately promoted SPEM development. Moreover, long-term treatment with recombinant WFDC2 was able to induce SPEM development. CONCLUSIONS WFDC2 expressed in response to gastric injury promotes SPEM through the up-regulation of IL33 expression. These findings provide novel insights into the role of WFDC2 in gastric carcinogenesis.
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Affiliation(s)
- Haengdueng Jeong
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Buhyun Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang H Kim
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | | | - Yejin Cho
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jeongeun Park
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yura Lee
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yeseul Oh
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Bo Ram Hwang
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Ah-Ra Jang
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Jong-Hwan Park
- Laboratory of Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea
| | - Ji-Ho Park
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Korea
| | - Daekee Lee
- Department of Life Science, Ewha Womans University, Seoul, Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Graduate School, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Korea.
| | - James R Goldenring
- Epithelial Biology Center and Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee.
| | - Ki Taek Nam
- Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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49
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Horita N, Keeley TM, Hibdon ES, Delgado E, Lafkas D, Siebel CW, Samuelson LC. Delta-like 1-Expressing Cells at the Gland Base Promote Proliferation of Gastric Antral Stem Cells in Mouse. Cell Mol Gastroenterol Hepatol 2021; 13:275-287. [PMID: 34438113 PMCID: PMC8599166 DOI: 10.1016/j.jcmgh.2021.08.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Notch pathway signaling maintains gastric epithelial cell homeostasis by regulating stem cell proliferation and differentiation. We previously identified NOTCH1 and NOTCH2 as the key Notch receptors controlling gastric stem cell function. Here, we identify the niche cells and critical Notch ligand responsible for regulating stem cell proliferation in the distal mouse stomach. METHODS Expression of Notch ligands in the gastric antrum was determined by quantitative reverse-transcriptase polymerase chain reaction and cellular localization was determined by in situ hybridization and immunostaining. The contribution of specific Notch ligands to regulate epithelial cell proliferation in adult mice was determined by inducible gene deletion, or by pharmacologic inhibition using antibodies directed against specific Notch ligands. Mouse gastric organoid cultures were used to confirm that Notch ligand signaling was epithelial specific. RESULTS Delta-like 1 (DLL1) and Jagged 1 (JAG1) were the most abundantly expressed Notch ligands in the adult mouse stomach, with DLL1 restricted to the antral gland base and JAG1 localized to the upper gland region. Inhibition of DLL1 alone or in combination with other Notch ligands significantly reduced epithelial cell proliferation and the growth of gastric antral organoids, while inhibition of the other Notch ligands, DLL4, JAG1, and JAG2, did not affect proliferation or organoid growth. Similarly, DLL1, and not DLL4, regulated proliferation of LGR5+ antral stem cells, which express the NOTCH1 receptor. CONCLUSIONS DLL1 is the key Notch ligand regulating epithelial cell proliferation in the gastric antrum. We propose that DLL1-expressing cells at the gland base are Notch niche cells that signal to adjacent LGR5+ antral stem cells to regulate stem cell proliferation and epithelial homeostasis.
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Affiliation(s)
- Nobukatsu Horita
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Theresa M Keeley
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Elise S Hibdon
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Elizabeth Delgado
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan
| | - Daniel Lafkas
- Department of Discovery Oncology, Genentech, San Francisco, California
| | | | - Linda C Samuelson
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
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50
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Sun MR, Steward AC, Sweet EA, Martin AA, Lipinski RJ. Developmental malformations resulting from high-dose maternal tamoxifen exposure in the mouse. PLoS One 2021; 16:e0256299. [PMID: 34403436 PMCID: PMC8370643 DOI: 10.1371/journal.pone.0256299] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/03/2021] [Indexed: 12/27/2022] Open
Abstract
Tamoxifen is an estrogen receptor (ER) ligand with widespread use in clinical and basic research settings. Beyond its application in treating ER-positive cancer, tamoxifen has been co-opted into a powerful approach for temporal-specific genetic alteration. The use of tamoxifen-inducible Cre-recombinase mouse models to examine genetic, molecular, and cellular mechanisms of development and disease is now prevalent in biomedical research. Understanding off-target effects of tamoxifen will inform its use in both clinical and basic research applications. Here, we show that prenatal tamoxifen exposure can cause structural birth defects in the mouse. Administration of a single 200 mg/kg tamoxifen dose to pregnant wildtype C57BL/6J mice at gestational day 9.75 caused cleft palate and limb malformations in the fetuses, including posterior digit duplication, reduction, or fusion. These malformations were highly penetrant and consistent across independent chemical manufacturers. As opposed to 200 mg/kg, a single dose of 50 mg/kg tamoxifen at the same developmental stage did not result in overt structural malformations. Demonstrating that prenatal tamoxifen exposure at a specific time point causes dose-dependent developmental abnormalities, these findings argue for more considerate application of tamoxifen in Cre-inducible systems and further investigation of tamoxifen’s mechanisms of action.
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Affiliation(s)
- Miranda R. Sun
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America
| | - Austin C. Steward
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America
| | - Emma A. Sweet
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America
| | - Alexander A. Martin
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America
| | - Robert J. Lipinski
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, United States of America
- * E-mail:
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