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Bai X, Ihara E, Tanaka Y, Minoda Y, Wada M, Hata Y, Esaki M, Ogino H, Chinen T, Ogawa Y. From bench to bedside: the role of gastrointestinal stem cells in health and disease. Inflamm Regen 2025; 45:15. [PMID: 40437566 PMCID: PMC12117945 DOI: 10.1186/s41232-025-00378-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 05/05/2025] [Indexed: 06/01/2025] Open
Abstract
The gastrointestinal (GI) tract constitutes a sophisticated system integral to digestion, nutrient absorption, and overall health, with its functionality predominantly hinging on the distinctive properties of diverse stem cell types. This review systematically investigates the pivotal roles of stem cells across the esophagus, stomach, small intestine, and colon, emphasizing their crucial contributions to tissue homeostasis, repair mechanisms, and regeneration. Each segment of the GI tract is characterized by specialized stem cell populations that exhibit distinct functional attributes, highlighting the necessity for tailored therapeutic approaches in the management of gastrointestinal disorders.Emerging research has shed light on the functional heterogeneity of GI stem cells, with ISCs in the small intestine displaying remarkable turnover rates and regenerative potential, whereas colonic stem cells (CSCs) are essential for the preservation of the colonic epithelial barrier. The intricate interplay between stem cells and their microenvironment-or niche-is fundamentally important for their functionality, with critical signaling pathways such as Wnt and Notch exerting substantial influence over stem cell behavior. The advent of organoid models derived from GI stem cells offers promising avenues for elucidating disease mechanisms and for the preclinical testing of novel therapeutic interventions.Despite notable advancements in foundational research on GI stem cells, the translation of these scientific discoveries into clinical practice remains limited. As of 2025, Japan's clinical GI disease guidelines do not endorse any stem cell-based therapies, underscoring the existing disconnect between research findings and clinical application. This scenario accentuates the urgent need for sustained efforts to bridge this divide and to cultivate innovative strategies that synergize stem cell technology with conventional treatment modalities.Future investigations should be directed toward unraveling the mechanisms that underpin stem cell dysfunction in various gastrointestinal pathologies, as well as exploring combination therapies that harness the regenerative capacities of stem cells in conjunction with immunomodulatory treatments. By fostering collaborative endeavors between basic researchers and clinical practitioners, we can deepen our understanding of GI stem cells and facilitate the translation of this knowledge into effective therapeutic interventions, ultimately enhancing patient outcomes in gastrointestinal diseases.
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Affiliation(s)
- Xiaopeng Bai
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Faculty of Health Sciences Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Canada
| | - Eikichi Ihara
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Yoshimasa Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yosuke Minoda
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Wada
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshitaka Hata
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mitsuru Esaki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Haruei Ogino
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takatoshi Chinen
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Hong F, Wang X, Zhong N, Zhang Z, Lin S, Zhang M, Li H, Liu Y, Wang Y, Zhao L, Yang X, Zhou H, Liang H, Chen YG. The critical role of BMP signaling in gastric epithelial cell differentiation revealed by organoids. CELL REGENERATION (LONDON, ENGLAND) 2025; 14:18. [PMID: 40377813 DOI: 10.1186/s13619-025-00237-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2025] [Revised: 05/04/2025] [Accepted: 05/06/2025] [Indexed: 05/18/2025]
Abstract
The efficient differentiation of adult gastric stem cells into specific epithelial cell types is crucial for gastric homeostasis. Although it is well appreciated that the niche plays a critical role in gastric epithelium cell differentiation, the relevant molecular factors and the underlying regulatory mechanisms remain poorly understood. In this study, by combining the knowledge of the niche cells obtained from single-cell RNA sequencing and manipulation of signaling pathways, we achieved effective differentiation of various gastric epithelial cell types in mouse and human gastric organoids. These in vitro differentiated cells showed a similar gene expression profile to those in gastric tissues. Specifically, BMP4 signaling stimulates pit cell and parietal cell differentiation. Furthermore, BMP4 and EGF signaling cooperate to enhance pit cell differentiation, whereas inhibition of TGF-β and BMP4 signaling promotes chief cell differentiation. We demonstrated that Zbtb7b is a novel regulator controlling pit cell differentiation. In addition, BMP4, together with the small molecule Isoxazole 9, promotes parietal and enteroendocrine cell differentiation. Our data also revealed the different requirements of parietal and chief cell differentiation between mouse and human. Together, our findings provide a mechanistic insight into gastric epithelial cell differentiation and uncover its similarities and differences between mouse and human, laying a foundation for future investigation and potential clinical use of gastric organoids.
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Affiliation(s)
- Fan Hong
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Xiaodan Wang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
- State Key Laboratory of Trauma, Burns and Combined Injury, Department of Shock and Transfusion, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China
| | - Nanshan Zhong
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China
| | - Ze Zhang
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Shibo Lin
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Mengxian Zhang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Haonan Li
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yalong Wang
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Lianzheng Zhao
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xiao Yang
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Hongwen Zhou
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Hui Liang
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ye-Guang Chen
- Guangzhou National Laboratory, Guangzhou, 510005, China.
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
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3
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He X, Lin S, Chen L, Huang Y, Hu J, Sun N. Antarctic Krill Protein Amyloid Fibrils as a Novel Iron Carrier for the Improvement of Iron Deficiency. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2025; 73:3170-3180. [PMID: 39851240 DOI: 10.1021/acs.jafc.4c11046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Iron fortification with food supplements remains the primary dietary strategy for improving iron deficiency anemia (IDA). This study used Antarctic krill protein for fibrillar design to form an Antarctic krill protein amyloid fibril (AKAF). The results indicated that peptides generated by proteolysis were a prerequisite for fibril assembly, forming elongated fibril structures and cross-linking upon heating. During this process, hydrogen bonds were rearranged, forming ordered β-sheet conformations (49.36 ± 0.21%); π-π stacking interactions among aromatic residues contributed to fibril formation. Further studies showed that AKAF effectively maintained iron in a bioavailable state and exhibited a high binding capacity (60.67 ± 0.69%). Moreover, the AKAF-iron complex markedly ameliorated hematological abnormalities in IDA mice, enhanced iron storage in the liver and spleen, and positively influenced the expression of iron homeostasis genes. This complex was also effective in alleviating gastric inflammatory responses induced by IDA. Overall, AKAF holds promise as an efficient iron delivery carrier.
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Affiliation(s)
- Xueqing He
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Songyi Lin
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
- Engineering Research Center of Special Dietary Food, the Education Department of Liaoning Province, Dalian 116034, P. R. China
| | - Lei Chen
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Yihan Huang
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Jinhui Hu
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
| | - Na Sun
- SKL of Marine Food Processing & Safety Control, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116034, China
- Engineering Research Center of Special Dietary Food, the Education Department of Liaoning Province, Dalian 116034, P. R. China
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Lee SH, Won Y, Gibbs D, Caldwell B, Goldstein A, Choi E, Goldenring JR. Amphiregulin Switches Progenitor Cell Fate for Lineage Commitment During Gastric Mucosal Regeneration. Gastroenterology 2024; 167:469-484. [PMID: 38492892 PMCID: PMC11260537 DOI: 10.1053/j.gastro.2024.03.009] [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: 11/07/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND & AIMS Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium. METHODS We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. Bromodeoxyuridine incorporation was used to trace newly generated cells during the injury and recovery phases. To define the epithelial lineage commitment process during recovery, we performed single-cell RNA-sequencing on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, using recombinant AREG treatment or AREG-deficient mice. RESULTS We determined that an epidermal growth factor receptor ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through single-cell RNA-sequencing and bromodeoxyuridine incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, transforming growth factor-α did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration but increases surface cell commitment. CONCLUSIONS These data demonstrate that different epidermal growth factor receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment.
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Affiliation(s)
- Su-Hyung Lee
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee.
| | - Yoonkyung Won
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David Gibbs
- Institute for Systems Biology, Seattle, Washington
| | - Brianna Caldwell
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anna Goldstein
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Eunyoung Choi
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
| | - James R Goldenring
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee; Nashville VA Medical Center, Nashville, Tennessee.
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5
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Arimura S, To S, Mills JC. Changing Fate: How EGFRs "Pit" Cell Versus Cell in the Stomach. Gastroenterology 2024; 167:441-442. [PMID: 38663820 DOI: 10.1053/j.gastro.2024.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 04/14/2024] [Indexed: 05/09/2024]
Affiliation(s)
- Sumimasa Arimura
- Section of Gastroenterology & Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Sarah To
- Section of Gastroenterology & Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Jason C Mills
- Section of Gastroenterology & Hepatology, Department of Medicine, Houston, Texas; Department of Pathology & Immunology, Houston, Texas; Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas.
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6
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Maubach G, Naumann M. Harnessing gastrointestinal organoids for cancer therapy. Trends Mol Med 2024; 30:617-619. [PMID: 38616435 DOI: 10.1016/j.molmed.2024.03.010] [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: 01/19/2024] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/16/2024]
Abstract
Gastrointestinal organoids have emerged as a model system that authentically recapitulates the in vivo situation. Despite biomedical and technical challenges, self-assembled 3D structures derived from pluripotent stem cells or healthy and diseased tissues have proved to be invaluable tools for cancer drug discovery, disease modeling, and studying infection with carcinogenic pathogens.
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Affiliation(s)
- Gunter Maubach
- Institute of Experimental Internal Medicine, Otto von Guericke University, 39104 Magdeburg, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University, 39104 Magdeburg, Germany.
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7
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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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8
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Liu YY, Wu DK, Chen JB, Tang YM, Jiang F. Advances in the study of gastric organoids as disease models. World J Gastrointest Oncol 2024; 16:1725-1736. [PMID: 38764838 PMCID: PMC11099456 DOI: 10.4251/wjgo.v16.i5.1725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/23/2024] [Accepted: 03/25/2024] [Indexed: 05/09/2024] Open
Abstract
Gastric organoids are models created in the laboratory using stem cells and sophisticated three-dimensional cell culture techniques. These models have shown great promise in providing valuable insights into gastric physiology and advanced disease research. This review comprehensively summarizes and analyzes the research advances in culture methods and techniques for adult stem cells and induced pluripotent stem cell-derived organoids, and patient-derived organoids. The potential value of gastric organoids in studying the pathogenesis of stomach-related diseases and facilitating drug screening is initially discussed. The construction of gastric organoids involves several key steps, including cell extraction and culture, three-dimensional structure formation, and functional expression. Simulating the structure and function of the human stomach by disease modeling with gastric organoids provides a platform to study the mechanism of gastric cancer induction by Helicobacter pylori. In addition, in drug screening and development, gastric organoids can be used as a key tool to evaluate drug efficacy and toxicity in preclinical trials. They can also be used for precision medicine according to the specific conditions of patients with gastric cancer, to assess drug resistance, and to predict the possibility of adverse reactions. However, despite the impressive progress in the field of gastric organoids, there are still many unknowns that need to be addressed, especially in the field of regenerative medicine. Meanwhile, the reproducibility and consistency of organoid cultures are major challenges that must be overcome. These challenges have had a significant impact on the development of gastric organoids. Nonetheless, as technology continues to advance, we can foresee more comprehensive research in the construction of gastric organoids. Such research will provide better solutions for the treatment of stomach-related diseases and personalized medicine.
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Affiliation(s)
- Yi-Yang Liu
- Graduate School, Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - De-Kun Wu
- Teaching Experiment and Training Center, Guangxi University of Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Ji-Bing Chen
- Central Laboratory, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - You-Ming Tang
- Department of Digestive Disease, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
| | - Feng Jiang
- AIDS Research Center, Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine, Nanning 530011, Guangxi Zhuang Autonomous Region, China
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Li K, Ma X, Li Z, Liu Y, Shen G, Luo Z, Wang D, Xia L, Wang Z, Tian M, Liu H, Geng F, Li B. A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2304326. [PMID: 38544338 PMCID: PMC11132046 DOI: 10.1002/advs.202304326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 02/08/2024] [Indexed: 05/29/2024]
Abstract
Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF-EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.
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Affiliation(s)
- Ke Li
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
- Bio‐X InstitutesShanghai Jiao Tong UniversityShanghai200240China
| | - Xiuying Ma
- Sichuan Engineering Research Center for Medicinal AnimalsSichuan Good Doctor Panxi Pharmaceutical Co., LtdChengdu610000China
| | - Zihao Li
- Bio‐X InstitutesShanghai Jiao Tong UniversityShanghai200240China
| | - Ya Liu
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
| | - Guiyan Shen
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
| | - Zecheng Luo
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
| | - Dong Wang
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
| | - Li Xia
- Department of PathophysiologyKey Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of EducationShanghai Jiao Tong University School of MedicineShanghai200025China
| | - Zhengting Wang
- Department of GastroenterologyRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200025China
| | - Ming Tian
- Department of BurnRuijin HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai200025China
| | - Huijuan Liu
- Bio‐X InstitutesShanghai Jiao Tong UniversityShanghai200240China
| | - Funeng Geng
- Sichuan Engineering Research Center for Medicinal AnimalsSichuan Good Doctor Panxi Pharmaceutical Co., LtdChengdu610000China
| | - Baojie Li
- Institute of Traditional Chinese Medicine and Stem Cell ResearchCollege of Basic Medical SciencesChengdu University of Traditional Chinese MedicineChengdu611137China
- Bio‐X InstitutesShanghai Jiao Tong UniversityShanghai200240China
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10
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Tong QY, Pang MJ, Hu XH, Huang XZ, Sun JX, Wang XY, Burclaff J, Mills JC, Wang ZN, Miao ZF. Gastric intestinal metaplasia: progress and remaining challenges. J Gastroenterol 2024; 59:285-301. [PMID: 38242996 DOI: 10.1007/s00535-023-02073-9] [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: 08/22/2023] [Accepted: 12/26/2023] [Indexed: 01/21/2024]
Abstract
Most gastric cancers arise in the setting of chronic inflammation which alters gland organization, such that acid-pumping parietal cells are lost, and remaining cells undergo metaplastic change in differentiation patterns. From a basic science perspective, recent progress has been made in understanding how atrophy and initial pyloric metaplasia occur. However, pathologists and cancer biologists have long been focused on the development of intestinal metaplasia patterns in this setting. Arguably, much less progress has been made in understanding the mechanisms that lead to the intestinalization seen in chronic atrophic gastritis and pyloric metaplasia. One plausible explanation for this disparity lies in the notable absence of reliable and reproducible small animal models within the field, which would facilitate the investigation of the mechanisms underlying the development of gastric intestinal metaplasia (GIM). This review offers an in-depth exploration of the current state of research in GIM, shedding light on its pivotal role in tumorigenesis. We delve into the histological subtypes of GIM and explore their respective associations with tumor formation. We present the current repertoire of biomarkers utilized to delineate the origins and progression of GIM and provide a comprehensive survey of the available, albeit limited, mouse lines employed for modeling GIM and engage in a discussion regarding potential cell lineages that serve as the origins of GIM. Finally, we expound upon the myriad signaling pathways recognized for their activity in GIM and posit on their potential overlap and interactions that contribute to the ultimate manifestation of the disease phenotype. Through our exhaustive review of the progression from gastric disease to GIM, we aim to establish the groundwork for future research endeavors dedicated to elucidating the etiology of GIM and developing strategies for its prevention and treatment, considering its potential precancerous nature.
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Affiliation(s)
- Qi-Yue Tong
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Min-Jiao Pang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xiao-Hai Hu
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xuan-Zhang Huang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Jing-Xu Sun
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Xin-Yu Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China
| | - Joseph Burclaff
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
- Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina, USA
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Departments of Pathology and Immunology, Molecular and Cellular Biology, Baylor College of Medicine, Houston, USA
| | - Zhen-Ning Wang
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
| | - Zhi-Feng Miao
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 N. Nanjing Street, Shenyang, 110001, Liaoning, China.
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11
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Liang Y, Yang Y, Nong R, Huang H, Chen X, Deng Y, Huang Z, Huang J, Cheng C, Ji M, Chen Y, Hu F. Do atrophic gastritis and intestinal metaplasia reverse after Helicobacter pylori eradication? Helicobacter 2024; 29:e13042. [PMID: 38018403 DOI: 10.1111/hel.13042] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND It's still controversial whether Helicobacter pylori (H. pylori) eradication can reverse atrophic gastritis (AG) and intestinal metaplasia (IM). Therefore, we performed a meta-analysis to estimate the effect of H. pylori eradication on AG and IM. METHODS We searched the PubMed, Web of Science and EMBASE datasets through April 2023 for epidemiological studies, which provided mean glandular atrophy (GA) or IM score before and after H. pylori eradication, or provided ORs, RRs or HRs and 95% CIs for the association of AG or IM with H. pylori eradication. Weighted mean difference (WMD) and pooled ORs and 95%CIs were used to estimate the effect of H. pylori eradication on AG and IM. RESULTS Twenty articles with a total of 5242 participants were included in this meta-analysis. H. pylori eradication significantly decreased GA score in the antrum (WMD -0.36; 95% CI: -0.52, -0.19, p < 0.01), GA score in the corpus (WMD -0.35; 95% CI: -0.52, -0.19, p < 0.01), IM score in the antrum (WMD -0.16; 95% CI: -0.26, -0.07, p < 0.01) and IM score in the corpus (WMD -0.20; 95% CI: -0.37, -0.04, p = 0.01). H. pylori eradication significantly improved AG (pooled OR 2.96; 95% CI: 1.70, 5.14, p < 0.01) and IM (pooled OR 2.41; 95% CI: 1.24, 4.70, p < 0.01). The association remained significant in the subgroup analyses by study design, sites of lesions, regions and follow-up time. Although Publication bias was observed for AG, the association remained significant after trim-and-fill adjustment. CONCLUSIONS H. pylori eradication could significantly improve AG and IM at early stage.
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Affiliation(s)
- Yongqiang Liang
- Department of Gastroenterology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, People's Republic of China
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
- 2019 Preventive Medicine, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
| | - Yuanhai Yang
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
- 2020 Preventive Medicine, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
| | - Ruiheng Nong
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
- 2020 Preventive Medicine, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
| | - Hao Huang
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
| | - Xiuyun Chen
- Department of Gastroenterology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Ying Deng
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
| | - Zhicong Huang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
| | - Jingyao Huang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
| | - Chunsheng Cheng
- Department of Gastroenterology and Endoscopy Centre, Huazhong University of Science and Technology Union Shenzhen Hospital (Nanshan Hospital) and The 6th Affiliated Hospital of Shenzhen University School of Medicine, Shenzhen, Guangdong, China
| | - Mingzhu Ji
- Department of Gastroenterology, Shenzhen Qianhai Shekou Free Trade Zone Hospital, Shenzhen, Guangdong, People's Republic of China
| | - Yinggang Chen
- National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Fulan Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
- Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen University Health Science Centre, Shenzhen, Guangdong, People's Republic of China
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12
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Vllahu M, Voli A, Licursi V, Zagami C, D’Amore A, Traulsen J, Woelffling S, Schmid M, Crickley R, Lisle R, Link A, Tosco A, Meyer TF, Boccellato F. Inflammation promotes stomach epithelial defense by stimulating the secretion of antimicrobial peptides in the mucus. Gut Microbes 2024; 16:2390680. [PMID: 39244776 PMCID: PMC11382725 DOI: 10.1080/19490976.2024.2390680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/30/2024] [Accepted: 08/05/2024] [Indexed: 09/10/2024] Open
Abstract
The mucus serves as a protective barrier in the gastrointestinal tract against microbial attacks. While its role extends beyond merely being a physical barrier, the extent of its active bactericidal properties remains unclear, and the mechanisms regulating these properties are not yet understood. We propose that inflammation induces epithelial cells to secrete antimicrobial peptides, transforming mucus into an active bactericidal agent. To investigate the properties of mucus, we previously developed mucosoid culture models that mimic the healthy human stomach epithelium. Similar to organoids, mucosoids are stem cell-driven cultures; however, the cells are cultivated on transwells at air-liquid interface. The epithelial cells of mucosoids form a polarized monolayer, allowing differentiation into all stomach lineages, including mucus-secreting cells. This setup facilitates the secretion and accumulation of mucus on the apical side of the mucosoids, enabling analysis of its bactericidal effects and protein composition, including antimicrobial peptides. Our findings show that TNFα, IL1β, and IFNγ induce the secretion of antimicrobials such as lactotransferrin, lipocalin2, complement component 3, and CXCL9 into the mucus. This antimicrobial-enriched mucus can partially eliminate Helicobacter pylori, a key stomach pathogen. The bactericidal activity depends on the concentration of each antimicrobial and their gene expression is higher in patients with inflammation and H.pylori-associated chronic gastritis. However, we also find that H. pylori infection can reduce the expression of antimicrobial encoding genes promoted by inflammation. These findings suggest that controlling antimicrobial secretion in the mucus is a critical component of epithelial immunity. However, pathogens like H. pylori can overcome these defenses and survive in the mucosa.
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Affiliation(s)
- Megi Vllahu
- Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Antonia Voli
- Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Valerio Licursi
- Institute of Molecular Biology and Pathology (IBPM), National Research Council (CNR) of Italy c/o Department of Biology and Biotechnology ‘‘C. Darwin’’, Sapienza University, Rome, Italy
| | - Claudia Zagami
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Antonella D’Amore
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Jan Traulsen
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Sara Woelffling
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Monika Schmid
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
| | - Robbie Crickley
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Richard Lisle
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany
| | - Alessandra Tosco
- Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy
| | - Thomas F. Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel and University Hospital Schleswig-Holstein - Campus Kiel, Kiel, Germany
| | - Francesco Boccellato
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
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13
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Wu Y, Guo Y, Huang T, Huang D, Liu L, Shen C, Jiang C, Wang Z, Chen H, Liang P, Hu Y, Zheng Z, Liang T, Zhai D, Zhu H, Liu Q. Licorice flavonoid alleviates gastric ulcers by producing changes in gut microbiota and promoting mucus cell regeneration. Biomed Pharmacother 2023; 169:115868. [PMID: 37952360 DOI: 10.1016/j.biopha.2023.115868] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/14/2023] Open
Abstract
Licorice flavonoid (LF) is the main component of Glycyrrhizae Radix et Rhizoma, a "medicine food homology" herbal medicine, which has anti-digestive ulcer activity, but the mechanism in anti-gastric ulcer (GU) remains to be elucidated. In this study, we manifested that LF increased the viability of human gastric mucosal epithelial (GES-1) cells, attenuated ethanol (EtOH)-induced manifestations, reduced histological injury, suppressed inflammation, and restored gastric mucosal barrier in GU rats. After LF therapy, the EtOH-induced gut dysbiosis was partly modulated, and short-chain fatty acids (SCFAs) like butyric acid, propionic acid, and valeric acid were found in higher concentrations. We discovered that the majority of genera that increased in the GU group had a negative correlation with SCFAs in the intestinal tract. In addition, LF-upregulated SCFAs boosted mucus secretion in the gastric epithelium and the expression of mucoprotein (MUC) 5AC and MUC6, particularly the MUC5AC in the gastric foveola. Moreover, LF triggered the EGFR/ERK signal pathway which promoted gastric mucus cell regeneration. Therefore, the findings indicated that LF could inhibit inflammation, promote mucosal barrier repair and angiogenesis, regulate gut microbiota and SCFA metabolism; more importantly, promote epithelial proliferation via activation of the EGFR/ERK pathway, exerting a protective and regenerative effect on the gastric mucosa.
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Affiliation(s)
- Yufan Wu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yinglin Guo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Tairun Huang
- Faculty of Chinese Medicines, Macau University of Science and Technology, Taipa, Macau
| | - Dehao Huang
- Huizhou Jiuhui Pharmaceutical Co., Ltd., Huizhou 516000, China
| | - Li Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Chunyan Shen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Cuiping Jiang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zhuxian Wang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Hongkai Chen
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Peiyi Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Yi Hu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Zeying Zheng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Tao Liang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Dan Zhai
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Hongxia Zhu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
| | - Qiang Liu
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
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14
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Manieri E, Tie G, Malagola E, Seruggia D, Madha S, Maglieri A, Huang K, Fujiwara Y, Zhang K, Orkin SH, Wang TC, He R, McCarthy N, Shivdasani RA. Role of PDGFRA + cells and a CD55 + PDGFRA Lo fraction in the gastric mesenchymal niche. Nat Commun 2023; 14:7978. [PMID: 38042929 PMCID: PMC10693581 DOI: 10.1038/s41467-023-43619-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 11/15/2023] [Indexed: 12/04/2023] Open
Abstract
PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA+ cells. Sub-epithelial PDGFRAHi myofibroblasts are principal sources of BMP ligands and two molecularly distinct pools distribute asymmetrically along antral glands but together fail to support epithelial growth in vitro. In contrast, PDGFRALo CD55+ cells strategically positioned beneath gastric glands promote epithelial expansion in the absence of other cells or factors. This population encompasses a small fraction expressing the BMP antagonist Grem1. Although Grem1+ cell ablation in vivo impairs intestinal stem cells, gastric stem cells are spared, implying that CD55+ cell activity in epithelial self-renewal derives from other subpopulations. Our findings shed light on spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for epithelial support.
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Affiliation(s)
- Elisa Manieri
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Guodong Tie
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Davide Seruggia
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- St. Anna Children's Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Shariq Madha
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Adrianna Maglieri
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Kun Huang
- Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Yuko Fujiwara
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Howard Hughes Medical Institute, Boston, MA, 02115, USA
| | - Kevin Zhang
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Stuart H Orkin
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Howard Hughes Medical Institute, Boston, MA, 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Ruiyang He
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Neil McCarthy
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Ramesh A Shivdasani
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
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15
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Gillis K, Orellana WA, Wilson E, Parnell TJ, Fort G, Dadzie HE, Zhang X, Snyder EL. FoxA1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.30.564775. [PMID: 37961260 PMCID: PMC10634937 DOI: 10.1101/2023.10.30.564775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we show that FoxA1/2 reprogram the epigenetic landscape of NKX2-1-negative LUAD to facilitate a gastric identity. After Nkx2-1 deletion, FoxA1/2 mediate demethylation of gastric-defining genes through recruitment of TET3, an enzyme that induces DNA demethylation. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of regulatory elements and their 3D interactions at gastric loci. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.
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16
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Tsubosaka A, Komura D, Kakiuchi M, Katoh H, Onoyama T, Yamamoto A, Abe H, Seto Y, Ushiku T, Ishikawa S. Stomach encyclopedia: Combined single-cell and spatial transcriptomics reveal cell diversity and homeostatic regulation of human stomach. Cell Rep 2023; 42:113236. [PMID: 37819756 DOI: 10.1016/j.celrep.2023.113236] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/05/2023] [Accepted: 09/24/2023] [Indexed: 10/13/2023] Open
Abstract
The stomach is an important digestive organ with various biological functions. However, because of the complexity of its cellular and glandular composition, its precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequencing (scRNA-seq) and subcellular-level spatial transcriptomics analysis of the human stomach and constructed the largest dataset to date: a stomach encyclopedia. This dataset consists of approximately 380,000 cells from scRNA-seq and the spatial transcriptome, enabling integrated analyses of transcriptional and spatial information of gastric and metaplastic cells. This analysis identified LEFTY1 as an uncharacterized stem cell marker, which was confirmed through lineage tracing analysis. A wide variety of cell-cell interactions between epithelial and stromal cells, including PDGFRA+BMP4+WNT5A+ fibroblasts, was highlighted in the developmental switch of intestinal metaplasia. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies of development, aging, and carcinogenesis.
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Affiliation(s)
- Ayumu Tsubosaka
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Daisuke Komura
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Miwako Kakiuchi
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Hiroto Katoh
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Takumi Onoyama
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan; Division of Gastroenterology and Nephrology, Department of Multidisciplinary Internal Medicine, School of Medicine, Faculty of Medicine, Tottori University, 36-1, Nishicho, Yonago 683-8504, Tottori, Japan
| | - Asami Yamamoto
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Hiroyuki Abe
- Dpartment of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-kyu 1130033, Tokyo, Japan
| | - Tetsuo Ushiku
- Dpartment of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku 1130033, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 1130033, Tokyo, Japan; Division of Pathology, National Cancer Center Exploratory Oncology Research & Clinical Trial Center, 6-5-1, Kashiwanoha, Kashiwa 277-8577, Chiba, Japan.
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17
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Alvina FB, Chen TCY, Lim HYG, Barker N. Gastric epithelial stem cells in development, homeostasis and regeneration. Development 2023; 150:dev201494. [PMID: 37746871 DOI: 10.1242/dev.201494] [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: 09/26/2023]
Abstract
The stem/progenitor cell pool is indispensable for the development, homeostasis and regeneration of the gastric epithelium, owing to its defining ability to self-renew whilst supplying the various functional epithelial lineages needed to digest food efficiently. A detailed understanding of the intricacies and complexities surrounding the behaviours and roles of these stem cells offers insights, not only into the physiology of gastric epithelial development and maintenance, but also into the pathological consequences following aberrations in stem cell regulation. Here, we provide an insightful synthesis of the existing knowledge on gastric epithelial stem cell biology, including the in vitro and in vivo experimental techniques that have advanced such studies. We highlight the contributions of stem/progenitor cells towards patterning the developing stomach, specification of the differentiated cell lineages and maintenance of the mature epithelium during homeostasis and following injury. Finally, we discuss gaps in our understanding and identify key research areas for future work.
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Affiliation(s)
- Fidelia B Alvina
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Tanysha Chi-Ying Chen
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Hui Yi Grace Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Nick Barker
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore 117593, Republic of Singapore
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18
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Beccaceci G, Sigal M. Unwelcome guests - the role of gland-associated Helicobacter pylori infection in gastric carcinogenesis. Front Oncol 2023; 13:1171003. [PMID: 37152042 PMCID: PMC10160455 DOI: 10.3389/fonc.2023.1171003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/04/2023] [Indexed: 05/09/2023] Open
Abstract
Helicobacter pylori (H. pylori) are Gram-negative bacteria that cause chronic gastritis and are considered the main risk factor for the development of gastric cancer. H. pylori have evolved to survive the harsh luminal environment of the stomach and are known to cause damage and signaling aberrations in gastric epithelial cells, which can result in premalignant and malignant pathology. As well as colonizing the gastric mucus and surface epithelial cells, a subpopulation of H. pylori can invade deep into the gastric glands and directly interact with progenitor and stem cells. Gland colonization therefore bears the potential to cause direct injury to long-lived cells. Moreover, this bacterial subpopulation triggers a series of host responses that cause an enhanced proliferation of stem cells. Here, we review recent insights into how gastric gland colonization by H. pylori is established, the resulting pro-carcinogenic epithelial signaling alterations, as well as new insights into stem cell responses to infection. Together these point towards a critical role of gland-associated H. pylori in the development of gastric cancer.
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Affiliation(s)
- Giulia Beccaceci
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Michael Sigal
- Medical Department, Division of Gastroenterology and Hepatology, Charité-Universtitätsmedizin Berlin, Berlin, Germany
- The Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
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19
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Manieri E, Tie G, Seruggia D, Madha S, Maglieri A, Huang K, Fujiwara Y, Zhang K, Orkin SH, He R, McCarthy N, Shivdasani RA. Defining the structure, signals, and cellular elements of the gastric mesenchymal niche. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.11.527728. [PMID: 36798304 PMCID: PMC9934611 DOI: 10.1101/2023.02.11.527728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
PDGFRA-expressing mesenchyme provides a niche for intestinal stem cells. Corresponding compartments are unknown in the stomach, where corpus and antral glandular epithelia have similar niche dependencies but are structurally distinct from the intestine and from each other. Previous studies considered antrum and corpus as a whole and did not assess niche functions. Using high-resolution imaging and sequencing, we identify regional subpopulations and niche properties of purified mouse corpus and antral PDGFRA + cells. PDGFRA Hi sub-epithelial myofibroblasts are principal sources of BMP ligands in both gastric segments; two molecularly distinct groups distribute asymmetrically along antral glands but together fail to support epithelial organoids in vitro . In contrast, strategically positioned PDGFRA Lo cells that express CD55 enable corpus and antral organoid growth in the absence of other cellular or soluble factors. Our study provides detailed insights into spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for stem cell support.
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20
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Liu F, Nong X, Qu W, Li X. Weikangling capsules combined with omeprazole ameliorates ethanol-induced chronic gastritis by regulating gut microbiota and EGF-EGFR-ERK pathway. Life Sci 2023; 315:121368. [PMID: 36623766 DOI: 10.1016/j.lfs.2023.121368] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/22/2022] [Accepted: 01/01/2023] [Indexed: 01/09/2023]
Abstract
AIMS Weikangling capsules (WKLCs) have been widely used in the treatment of chronic gastritis. Whether used alone or combined with omeprazole (OME), it shows a significant effect. However, the mechanisms haven't been established. The study aimed to explore the mechanisms of WKLCs and its combination with OME on chronic gastritis. MAIN METHODS The components of WKLCs and EA (the ethyl acetate extraction extracted from WKLCs) fraction were analyzed. Then chronic gastritis model rats were induced by 56 % ethanol and treated with OME, low dose of WKLCs (WKL), high dose of WKLCs (WKH), WKLCs combined with OME (WO), and EA fraction (EA) to evaluate the mechanisms of WKLCs, drug combination and EA fraction. KEY FINDINGS A total of 22 components of WKLCs were quantified, among them 18 were enriched in EA fraction. WKLCs alleviated the morphology and inflammation of gastric mucosa and downregulated the levels of inflammatory factors (IL-1β, TNF-α, IL-6) and epidermal growth factor (EGF) in serum by inhibiting the EGF-EGFR-ERK pathway, regulating gut microbiota composition and SCFAs contents in feces. WKLCs plus OME was better than OME. EA fraction improved digestive function by increasing pepsin activity and decreasing gastrointestinal hormones (GAS and VIP) compared with WKLCs. SIGNIFICANCE This study elucidated that the effect of WKLCs and its combination with OME in the treatment of chronic gastritis was attributed to regulating the composition of the gut microbiota and inhibiting the EGF-EGFR-ERK pathway. The EA fraction is an inseparable effective substance of WKLCs. This study provides scientific evidence for clinical application.
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Affiliation(s)
- Feng Liu
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Xiaojing Nong
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
| | - Wenhua Qu
- Heilongjiang Sunflower Pharmaceutical Co. Ltd., Heilongjiang 150070, China
| | - Xiaobo Li
- School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.
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21
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Wizenty J, Sigal M. Gastric Stem Cell Biology and Helicobacter pylori Infection. Curr Top Microbiol Immunol 2023; 444:1-24. [PMID: 38231213 DOI: 10.1007/978-3-031-47331-9_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: 01/18/2024]
Abstract
Helicobacter pylori colonizes the human gastric mucosa and persists lifelong. An interactive network between the bacteria and host cells shapes a unique microbial niche within gastric glands that alters epithelial behavior, leading to pathologies such as chronic gastritis and eventually gastric cancer. Gland colonization by the bacterium initiates aberrant trajectories by inducing long-term inflammatory and regenerative gland responses, which involve various specialized epithelial and stromal cells. Recent studies using cell lineage tracing, organoids and scRNA-seq techniques have significantly advanced our knowledge of the molecular "identity" of epithelial and stromal cell subtypes during normal homeostasis and upon infection, and revealed the principles that underly stem cell (niche) behavior under homeostatic conditions as well as upon H. pylori infection. The activation of long-lived stem cells deep in the gastric glands has emerged as a key prerequisite of H. pylori-associated gastric site-specific pathologies such as hyperplasia in the antrum, and atrophy or metaplasia in the corpus, that are considered premalignant lesions. In addition to altering the behaviour of bona fide stem cells, injury-driven de-differentiation and trans-differentation programs, such as "paligenosis", subsequently allow highly specialized secretory cells to re-acquire stem cell functions, driving gland regeneration. This plastic regenerative capacity of gastric glands is required to maintain homeostasis and repair mucosal injuries. However, these processes are co-opted in the context of stepwise malignant transformation in chronic H. pylori infection, causing the emergence, selection and expansion of cancer-promoting stem cells.
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Affiliation(s)
- Jonas Wizenty
- Division of Gastroenterology and Hepatology, Medical Department, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Sigal
- Division of Gastroenterology and Hepatology, Medical Department, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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22
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Fritsche K, Boccellato F, Schlaermann P, Koeppel M, Denecke C, Link A, Malfertheiner P, Gut I, Meyer TF, Berger H. DNA methylation in human gastric epithelial cells defines regional identity without restricting lineage plasticity. Clin Epigenetics 2022; 14:193. [PMID: 36585699 PMCID: PMC9801550 DOI: 10.1186/s13148-022-01406-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 12/13/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Epigenetic modifications in mammalian DNA are commonly manifested by DNA methylation. In the stomach, altered DNA methylation patterns have been observed following chronic Helicobacter pylori infections and in gastric cancer. In the context of epigenetic regulation, the regional nature of the stomach has been rarely considered in detail. RESULTS Here, we establish gastric mucosa derived primary cell cultures as a reliable source of native human epithelium. We describe the DNA methylation landscape across the phenotypically different regions of the healthy human stomach, i.e., antrum, corpus, fundus together with the corresponding transcriptomes. We show that stable regional DNA methylation differences translate to a limited extent into regulation of the transcriptomic phenotype, indicating a largely permissive epigenetic regulation. We identify a small number of transcription factors with novel region-specific activity and likely epigenetic impact in the stomach, including GATA4, IRX5, IRX2, PDX1 and CDX2. Detailed analysis of the Wnt pathway reveals differential regulation along the craniocaudal axis, which involves non-canonical Wnt signaling in determining cell fate in the proximal stomach. By extending our analysis to pre-neoplastic lesions and gastric cancers, we conclude that epigenetic dysregulation characterizes intestinal metaplasia as a founding basis for functional changes in gastric cancer. We present insights into the dynamics of DNA methylation across anatomical regions of the healthy stomach and patterns of its change in disease. Finally, our study provides a well-defined resource of regional stomach transcription and epigenetics.
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Affiliation(s)
- Kristin Fritsche
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany
| | - Francesco Boccellato
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Philipp Schlaermann
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany
| | - Max Koeppel
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany
| | - Christian Denecke
- Center for Bariatric and Metabolic Surgery, Center of Innovative Surgery (ZIC), Department of Surgery, Campus Virchow Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Alexander Link
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von-Guericke University Hospital, Magdeburg, Germany
| | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-Von-Guericke University Hospital, Magdeburg, Germany
| | - Ivo Gut
- Centro Nacional de Análisis Genómico (CNAG-CRG), Barcelona, Spain
| | - Thomas F Meyer
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel and University Hospital Schleswig-Holstein - Campus Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.
| | - Hilmar Berger
- Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
- Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian Albrecht University of Kiel and University Hospital Schleswig-Holstein - Campus Kiel, Rosalind-Franklin-Straße 12, 24105, Kiel, Germany.
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23
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Gao Y, Dong J, Qi S, Zhou X, Wu X, Wang W, Wen L, Fu W, Tang F. Establishment and characterization of adult human gastric epithelial progenitor‐like cell lines. Cell Prolif 2022:e13355. [PMID: 36331058 DOI: 10.1111/cpr.13355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/23/2022] [Accepted: 10/06/2022] [Indexed: 11/06/2022] Open
Affiliation(s)
- Yuan Gao
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Peking‐Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies Peking University Beijing China
- Beijing Advanced Innovation Center for Genomics Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Beijing China
| | - Ji Dong
- Guangzhou Laboratory Guangzhou China
| | - Shuyue Qi
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Beijing Advanced Innovation Center for Genomics Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Beijing China
| | - Xin Zhou
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Peking University Third Hospital Cancer Center Peking University Third Hospital Beijing China
| | - Xinglong Wu
- College of Animal Science and Technology Hebei Agricultural University Baoding Hebei China
| | - Wendong Wang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Peking University Third Hospital Cancer Center Peking University Third Hospital Beijing China
| | - Lu Wen
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Beijing Advanced Innovation Center for Genomics Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Beijing China
| | - Wei Fu
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Peking University Third Hospital Cancer Center Peking University Third Hospital Beijing China
| | - Fuchou Tang
- School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery Third Hospital, Peking University Beijing China
- Peking‐Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies Peking University Beijing China
- Beijing Advanced Innovation Center for Genomics Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Beijing China
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24
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Takabayashi H, Ji T, Peng L, Li X, Shinohara M, Mao M, Eaton KA, Shah YM, Todisco A. Regulation of Parietal Cell Homeostasis by Bone Morphogenetic Protein Signaling. GASTRO HEP ADVANCES 2022; 2:221-231. [PMID: 39132621 PMCID: PMC11307507 DOI: 10.1016/j.gastha.2022.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 10/04/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Loss of bone morphogenetic protein (BMP) signaling in the stomach, achieved by transgenic expression of the BMP inhibitor noggin (H + /K + -Nog mice), causes parietal cell (PC) loss, spasmolytic polypeptide-expressing metaplasia, a marker of preneoplasia, and activation of cell proliferation. We examined if specific inhibition of BMP signaling in PCs leads to aberrations in epithelial homeostasis. Methods Mice with floxed alleles of BMP receptor 1a (Bmpr1a flox/flox mice) were crossed to H + /K + -Cre mice to generate H + /K + -Cre;Bmpr1a flox/flox mice. Morphology of the mucosa was analyzed by hematoxylin and eosin staining. Distribution of H+/K+-ATPase-, IF-, and Ki-67-positive cells was analyzed by immunostaining. Expression of pit and neck cell mucins was determined by staining with the lectins Ulex Europaeus Agglutinin 1 and Griffonia (Bandeiraea) simplicifolia lectin II, respectively. Isolation of PCs from control and Nog-expressing mice was achieved by crossing H + /K + -Nog mice to Rosa26-tdTomato (Tom) mice to generate H + /K + -Nog;Rosa26-tdTom mice. H + /K + -Cre mice were then crossed to H + /K + -Nog;Rosa26-tdTom mice to generate H + /K + -Cre;H + /K + -Nog;Rosa26-tdTom mice. Tom-labeled PCs were purified by flow cytometry. Changes in PC transcripts were measured by RNA-Seq. Results Six-month-old H + /K + -Cre;Bmpr1a flox/flox mice exhibited increased epithelial cell proliferation, presence of transitional cells showing colocalization of IF with both Griffonia (Bandeiraea) simplicifolia lectin II-binding mucins and the H+/K+-ATPase, and expansion of Ulex Europaeus Agglutinin 1-positive cells. PC transcripts from Nog-expressing mice demonstrated induction of markers of Spasmolytic Polypeptide-Expressing Metaplasia. Conclusion PC-specific loss of BMP signaling alters the homeostasis of the gastric epithelium leading to the development of metaplasia.
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Affiliation(s)
- Hidehiko Takabayashi
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Tuo Ji
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Lei Peng
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xuan Li
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Masahiko Shinohara
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Maria Mao
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Kathryn A. Eaton
- Department of Microbiology and Immunology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Yatrik M. Shah
- Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, Michigan
| | - Andrea Todisco
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan
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25
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Wang Q, Guo F, Jin Y, Ma Y. Applications of human organoids in the personalized treatment for digestive diseases. Signal Transduct Target Ther 2022; 7:336. [PMID: 36167824 PMCID: PMC9513303 DOI: 10.1038/s41392-022-01194-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 08/09/2022] [Accepted: 09/13/2022] [Indexed: 11/15/2022] Open
Abstract
Digestive system diseases arise primarily through the interplay of genetic and environmental influences; there is an urgent need in elucidating the pathogenic mechanisms of these diseases and deploy personalized treatments. Traditional and long-established model systems rarely reproduce either tissue complexity or human physiology faithfully; these shortcomings underscore the need for better models. Organoids represent a promising research model, helping us gain a more profound understanding of the digestive organs; this model can also be used to provide patients with precise and individualized treatment and to build rapid in vitro test models for drug screening or gene/cell therapy, linking basic research with clinical treatment. Over the past few decades, the use of organoids has led to an advanced understanding of the composition of each digestive organ and has facilitated disease modeling, chemotherapy dose prediction, CRISPR-Cas9 genetic intervention, high-throughput drug screening, and identification of SARS-CoV-2 targets, pathogenic infection. However, the existing organoids of the digestive system mainly include the epithelial system. In order to reveal the pathogenic mechanism of digestive diseases, it is necessary to establish a completer and more physiological organoid model. Combining organoids and advanced techniques to test individualized treatments of different formulations is a promising approach that requires further exploration. This review highlights the advancements in the field of organoid technology from the perspectives of disease modeling and personalized therapy.
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Affiliation(s)
- Qinying Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Fanying Guo
- School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yutao Jin
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yanlei Ma
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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26
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Idowu S, Bertrand PP, Walduck AK. Gastric organoids: Advancing the study of H. pylori pathogenesis and inflammation. Helicobacter 2022; 27:e12891. [PMID: 35384141 PMCID: PMC9287064 DOI: 10.1111/hel.12891] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/14/2022] [Accepted: 03/20/2022] [Indexed: 12/13/2022]
Abstract
For decades, traditional in vitro and in vivo models used for the study of Helicobacter pylori infection have relied heavily on the use of gastric cancer cell lines and rodents. Major challenges faced by these methods have been the inability to study cancer initiation in already cancerous cell lines, and the difficulty in translating results obtained in animal models due to genetic differences. These challenges have prevented a thorough understanding of the pathogenesis of disease and slowed the development of cancer therapies and a suitable vaccine against the pathogen. In recent years, the development of gastric organoids has provided great advantages over the traditional in vivo and in vitro models due to their similarities to the human stomach in vivo, their ease of use, and the capacity for long-term culture. This review discusses the advantages and limitations of existing in vivo and in vitro models of H. pylori infection, and how gastric organoids have been applied to study H. pylori pathogenesis, with a focus on how the pathogen interacts with the gastric epithelium, inflammatory processes, epithelial repair, and cancer initiation. The potential applications of organoids to address more complex questions on the role of hormones, vaccine-induced immunity are also discussed.
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27
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Hautefort I, Poletti M, Papp D, Korcsmaros T. Everything You Always Wanted to Know About Organoid-Based Models (and Never Dared to Ask). Cell Mol Gastroenterol Hepatol 2022; 14:311-331. [PMID: 35643188 PMCID: PMC9233279 DOI: 10.1016/j.jcmgh.2022.04.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 12/12/2022]
Abstract
Homeostatic functions of a living tissue, such as the gastrointestinal tract, rely on highly sophisticated and finely tuned cell-to-cell interactions. These crosstalks evolve and continuously are refined as the tissue develops and give rise to specialized cells performing general and tissue-specific functions. To study these systems, stem cell-based in vitro models, often called organoids, and non-stem cell-based primary cell aggregates (called spheroids) appeared just over a decade ago. These models still are evolving and gaining complexity, making them the state-of-the-art models for studying cellular crosstalk in the gastrointestinal tract, and to investigate digestive pathologies, such as inflammatory bowel disease, colorectal cancer, and liver diseases. However, the use of organoid- or spheroid-based models to recapitulate in vitro the highly complex structure of in vivo tissue remains challenging, and mainly restricted to expert developmental cell biologists. Here, we condense the founding knowledge and key literature information that scientists adopting the organoid technology for the first time need to consider when using these models for novel biological questions. We also include information that current organoid/spheroid users could use to add to increase the complexity to their existing models. We highlight the current and prospective evolution of these models through bridging stem cell biology with biomaterial and scaffold engineering research areas. Linking these complementary fields will increase the in vitro mimicry of in vivo tissue, and potentially lead to more successful translational biomedical applications. Deepening our understanding of the nature and dynamic fine-tuning of intercellular crosstalks will enable identifying novel signaling targets for new or repurposed therapeutics used in many multifactorial diseases.
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Affiliation(s)
- Isabelle Hautefort
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom
| | - Martina Poletti
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom; Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom
| | - Diana Papp
- Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom
| | - Tamas Korcsmaros
- Earlham Institute, Organisms and Ecosystems Programme, Norwich, United Kingdom; Quadram Institute Bioscience, Gut Microbes and Health Programme, Norwich, United Kingdom; Imperial College London, Department of Metabolism, Digestion and Reproduction, London, United Kingdom.
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28
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Hoffmann W. Self-Renewal and Cancers of the Gastric Epithelium: An Update and the Role of the Lectin TFF1 as an Antral Tumor Suppressor. Int J Mol Sci 2022; 23:ijms23105377. [PMID: 35628183 PMCID: PMC9141172 DOI: 10.3390/ijms23105377] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/16/2022] Open
Abstract
In 2020, gastric cancer was the fourth leading cause of cancer deaths globally. About 90% of gastric cancers are sporadic and the vast majority are correlated with Helicobacter pylori infection; whereas familial clustering is observed in about 10% of cases. Gastric cancer is now considered to be a disease originating from dysregulated self-renewal of the gastric glands in the setting of an inflammatory environment. The human stomach contains two types of gastric units, which show bi-directional self-renewal from a complex variety of stem cells. This review focuses on recent progress concerning the characterization of the different stem cell populations and the mainly mesenchymal signals triggering their stepwise differentiation as well as the genesis of pre-cancerous lesions and carcinogenesis. Furthermore, a model is presented (Lectin-triggered Receptor Blocking Hypothesis) explaining the role of the lectin TFF1 as an antral tumor suppressor possibly regulating Lgr5+ antral stem cells in a paracrine or maybe autocrine fashion, with neighboring antral gland cells having a role as niche cells.
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Affiliation(s)
- Werner Hoffmann
- Institute of Molecular Biology and Medicinal Chemistry, Otto-von-Guericke University Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany
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29
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Morphogen Signals Shaping the Gastric Glands in Health and Disease. Int J Mol Sci 2022; 23:ijms23073632. [PMID: 35408991 PMCID: PMC8998987 DOI: 10.3390/ijms23073632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/21/2022] [Accepted: 03/23/2022] [Indexed: 12/17/2022] Open
Abstract
The adult gastric mucosa is characterised by deep invaginations of the epithelium called glands. These tissue architectural elements are maintained with the contribution of morphogen signals. Morphogens are expressed in specific areas of the tissue, and their diffusion generates gradients in the microenvironment. Cells at different positions in the gland sense a specific combination of signals that instruct them to differentiate, proliferate, regenerate, or migrate. Differentiated cells perform specific functions involved in digestion, such as the production of protective mucus and the secretion of digestive enzymes or gastric acid. Biopsies from gastric precancerous conditions usually display tissue aberrations and change the shape of the glands. Alteration of the morphogen signalling microenvironment is likely to underlie those conditions. Furthermore, genes involved in morphogen signalling pathways are found to be frequently mutated in gastric cancer. We summarise the most recent findings regarding alterations of morphogen signalling during gastric carcinogenesis, and we highlight the new stem cell technologies that are improving our understanding of the regulation of human tissue shape.
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30
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Idowu S, Bertrand PP, Walduck AK. Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer. Int J Mol Sci 2022; 23:2790. [PMID: 35269931 PMCID: PMC8911327 DOI: 10.3390/ijms23052790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.
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Affiliation(s)
| | | | - Anna K. Walduck
- STEM College, RMIT University, Melbourne, VIC 3000, Australia; (S.I.); (P.P.B.)
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31
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Maubach G, Vieth M, Boccellato F, Naumann M. Helicobacter pylori-induced NF-κB: trailblazer for gastric pathophysiology. Trends Mol Med 2022; 28:210-222. [PMID: 35012886 DOI: 10.1016/j.molmed.2021.12.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
NF-κB signaling pathways, induced by a variety of triggers, play a key role in regulating the expression of genes involved in the immune response and cellular responses to stress. The human pathogen Helicobacter pylori induces classical and alternative NF-κB signaling pathways via its effector ADP-L-glycero-β-D-manno-heptose (ADP-heptose). We review H. pylori- and NF-κB-dependent alterations in cellular processes and associated maladaptation leading to deleterious gastric pathophysiology that have implications for the diagnosis and treatment of gastric diseases. Therapeutic options for gastric cancer (GC) include clinically relevant small molecule inhibitors of NF-κB and epigenetic therapy approaches. In this context, gastric organoid biobanks originated from patient material, represent a valuable platform for translational applications to predict patient responses to chemotherapy, with a view to personalized medicine.
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Affiliation(s)
- Gunter Maubach
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Friedrich Alexander University, Erlangen-Nuremberg, 95445 Bayreuth, Germany
| | - Francesco Boccellato
- Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, OX37DQ Oxford, UK
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University Magdeburg, 39120 Magdeburg, Germany.
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Gastritis, Gastric Polyps and Gastric Cancer. Int J Mol Sci 2021; 22:ijms22126548. [PMID: 34207192 PMCID: PMC8234857 DOI: 10.3390/ijms22126548] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis.
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