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Iqbal S, Rezaul Karim M, Yang DC, Mathiyalagan R, Chan Kang S. Tuft cells - the immunological interface and role in disease regulation. Int Immunopharmacol 2023; 118:110018. [PMID: 36989894 DOI: 10.1016/j.intimp.2023.110018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 02/09/2023] [Accepted: 03/07/2023] [Indexed: 03/29/2023]
Abstract
Tuft cells, also known as taste chemosensory cells, accumulate during parasite colonization or infection and have powerful immunomodulatory effects on substances that could be detrimental, as well as possible anti-inflammatory or antibacterial effects. Tuft cells are the primary source of interleukin (IL)-25. They trigger extra Innate lymphoid type-2 cells (ILC2) in the intestinal lamina propria to create cytokines (type 2); for instance, IL-13, which leads to an increase in IL-25. As tuft cells can produce biological effector molecules, such as IL-25 and eicosanoids involved in allergy (for example, cysteinyl leukotrienes and prostaglandin D2) and the neurotransmitter acetylcholine. Following parasite infection, tuft cells require transient receptor potential cation channel subfamily M member 5 (TRPM5)-dependent chemosensation to produce responses. Secretory tuft cells provide a physical mucus barrier against the external environment and therefore have vital defensive roles against diseases by supporting tissue maintenance and repair. In addition to recent research on tuft cells, more studies are required to understand the distribution, cell turnover, molecular characteristics, responses in various species, involvement in immunological function across tissues, and most importantly, the mechanism involved in the control of various diseases.
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Affiliation(s)
- Safia Iqbal
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Department of Microbiology, Varendra Institute of Biosciences, Affiliated by Rajshahi University, Natore, Rajshahi, Bangladesh.
| | - Md Rezaul Karim
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia 7003, Bangladesh.
| | - Deok-Chun Yang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
| | - Ramya Mathiyalagan
- Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
| | - Se Chan Kang
- Department of Biopharmaceutical Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea; Graduate School of Biotechnology, College of Life Science, Kyung Hee University, Yongin-si, Gyeonggi-do 17104, Korea.
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Sáenz JB, Mills JC. Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 2018; 15:257-273. [PMID: 29463907 PMCID: PMC6016373 DOI: 10.1038/nrgastro.2018.5] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Subjected to countless daily injuries, the stomach still functions as a remarkably efficient digestive organ and microbial filter. In this Review, we follow the lead of the earliest gastroenterologists who were fascinated by the antiseptic and digestive powers of gastric secretions. We propose that it is easiest to understand how the stomach responds to injury by stressing the central role of the most important gastric secretion, acid. The stomach follows two basic patterns of adaptation. The superficial response is a pattern whereby the surface epithelial cells migrate and rapidly proliferate to repair erosions induced by acid or other irritants. The stomach can also adapt through a glandular response when the source of acid is lost or compromised (that is, the process of oxyntic atrophy). We primarily review the mechanisms governing the glandular response, which is characterized by a metaplastic change in cellular differentiation known as spasmolytic polypeptide-expressing metaplasia (SPEM). We propose that the stomach, like other organs, exhibits marked cellular plasticity: the glandular response involves reprogramming mature cells to serve as auxiliary stem cells that replace lost cells. Unfortunately, such plasticity might mean that the gastric epithelium undergoes cycles of differentiation and de-differentiation that increase the risk of accumulating cancer-predisposing mutations.
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Affiliation(s)
- José B. Sáenz
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
| | - Jason C. Mills
- Division of Gastroenterology, Department of Internal Medicine, Washington University School of Medicine
- Department of Developmental Biology, Washington University School of Medicine
- Department of Pathology and Immunology, Washington University School of Medicine
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Selective and reversible suppression of intestinal stem cell differentiation by pharmacological inhibition of BET bromodomains. Sci Rep 2016; 6:20390. [PMID: 26856877 PMCID: PMC4746593 DOI: 10.1038/srep20390] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 12/31/2015] [Indexed: 12/13/2022] Open
Abstract
Absorptive and secretory cells of the small intestine are derived from a single population of Lgr5-expressing stem cells. While key genetic pathways required for differentiation into specific lineages have been defined, epigenetic programs contributing to this process remain poorly characterized. Members of the BET family of chromatin adaptors contain tandem bromodomains that mediate binding to acetylated lysines on target proteins to regulate gene expression. In this study, we demonstrate that mice treated with a small molecule inhibitor of BET bromodomains, CPI203, exhibit greater than 90% decrease in tuft and enteroendocrine cells in both crypts and villi of the small intestine, with no changes observed in goblet or Paneth cells. BET bromodomain inhibition did not alter the abundance of Lgr5-expressing stem cells in crypts, but rather exerted its effects on intermediate progenitors, in part through regulation of Ngn3 expression. When BET bromodomain inhibition was combined with the chemotherapeutic gemcitabine, pervasive apoptosis was observed in intestinal crypts, revealing an important role for BET bromodomain activity in intestinal homeostasis. Pharmacological targeting of BET bromodomains defines a novel pathway required for tuft and enteroendocrine differentiation and provides an important tool to further dissect the progression from stem cell to terminally differentiated secretory cell.
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Ong BA, Vega KJ, Houchen CW. Intestinal stem cells and the colorectal cancer microenvironment. World J Gastroenterol 2014; 20:1898-1909. [PMID: 24587669 PMCID: PMC3934460 DOI: 10.3748/wjg.v20.i8.1898] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 12/03/2013] [Accepted: 01/05/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) remains a highly fatal condition in part due to its resilience to treatment and its propensity to spread beyond the site of primary occurrence. One possible avenue for cancer to escape eradication is via stem-like cancer cells that, through phenotypic heterogeneity, are more resilient than other tumor constituents and are key contributors to cancer growth and metastasis. These proliferative tumor cells are theorized to possess many properties akin to normal intestinal stem cells. Not only do these CRC “stem” cells demonstrate similar restorative ability, they also share many cell pathways and surface markers in common, as well as respond to the same key niche stimuli. With the improvement of techniques for epithelial stem cell identification, our understanding of CRC behavior is also evolving. Emerging evidence about cellular plasticity and epithelial mesenchymal transition are shedding light onto metastatic CRC processes and are also challenging fundamental concepts about unidirectional epithelial proliferation. This review aims to reappraise evidence supporting the existence and behavior of CRC stem cells, their relationship to normal stem cells, and their possible dependence on the stem cell niche.
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Singh SR. Gastric cancer stem cells: a novel therapeutic target. Cancer Lett 2013; 338:110-9. [PMID: 23583679 DOI: 10.1016/j.canlet.2013.03.035] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 03/25/2013] [Accepted: 03/30/2013] [Indexed: 12/14/2022]
Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer.
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Affiliation(s)
- Shree Ram Singh
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
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Hübner S, Efthymiadis A. Recent progress in histochemistry and cell biology. Histochem Cell Biol 2012; 137:403-57. [PMID: 22366957 DOI: 10.1007/s00418-012-0933-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2012] [Indexed: 01/06/2023]
Abstract
Studies published in Histochemistry and Cell Biology in the year 2011 represent once more a manifest of established and newly sophisticated techniques being exploited to put tissue- and cell type-specific molecules into a functional context. The review is therefore the Histochemistry and Cell Biology's yearly intention to provide interested readers appropriate summaries of investigations touching the areas of tissue biology, developmental biology, the biology of the immune system, stem cell research, the biology of subcellular compartments, in order to put the message of such studies into natural scientific-/human- and also pathological-relevant correlations.
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Affiliation(s)
- Stefan Hübner
- Institute of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
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Hirshoren N, Cohen J, Neuman T, Weinberger JM, Eliashar R. DCLK1 expression in gastrointestinal stem cells and neoplasia. ACTA ACUST UNITED AC 2012. [DOI: 10.7243/2049-7962-1-12] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Gastric tuft cells express DCLK1 and are expanded in hyperplasia. Histochem Cell Biol 2011; 136:191-204. [PMID: 21688022 DOI: 10.1007/s00418-011-0831-1] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2011] [Indexed: 01/10/2023]
Abstract
Epithelial tuft cells are named after their characteristic microtubule bundles located at the cell apex where these are exposed to the luminal environment. As such, tuft cells are found in multiple organs, including the gastrointestinal (GI) tract where the apical "tuft" is hypothesized to detect and transmit environmental signals. Thus, the goal of our study was to characterize gastric tuft cells during GI tract development, then subsequently in the normal and metaplastic adult stomach. GI tracts from mouse embryos, and newborn and postnatal mice were analyzed. Tuft cells were identified by immunohistochemistry using acetylated-α-tubulin (acTub) antibody to detect the microtubule bundle. Additional tuft cell markers, e.g., doublecortin-like kinase 1 (DCLK1), were used to co-localize with acTub. Tuft cells were quantified in human gastric tissue arrays and in mouse stomachs with or without inflammation. In the developing intestine, tuft cells in both the crypts and villi expressed all markers by E18.5. In the stomach, acTub co-localized with DCLK1 and other established tuft cell markers by E18.5 in the antrum, but not until postnatal day 7 in the corpus, with the highest density of tuft cells clustered at the forestomach ridge. Tuft cell numbers increased in hyperplastic human and mouse stomachs. In the adult GI tract, the tuft cell marker acTub co-expressed with DCKL1 and chemosensory markers, e.g.,TRPM5. In summary, tuft cells appear in the gastric antrum and intestine at E18.5, but their maximal numbers in the corpus are not achieved until after weaning. Tuft cell numbers increase with inflammation, hyperplasia, and metaplasia.
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Speer AL, Sala FG, Matthews JA, Grikscheit TC. Murine tissue-engineered stomach demonstrates epithelial differentiation. J Surg Res 2011; 171:6-14. [PMID: 21571313 DOI: 10.1016/j.jss.2011.03.062] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2011] [Revised: 02/26/2011] [Accepted: 03/22/2011] [Indexed: 12/30/2022]
Abstract
BACKGROUND Gastric cancer remains the second largest cause of cancer-related mortality worldwide. Postgastrectomy morbidity is considerable and quality of life is poor. Tissue-engineered stomach is a potential replacement solution to restore adequate food reservoir and gastric physiology. In this study, we performed a detailed investigation of the development of tissue-engineered stomach in a mouse model, specifically evaluating epithelial differentiation, proliferation, and the presence of putative stem cell markers. MATERIALS AND METHODS Organoid units were isolated from <3 wk-old mouse glandular stomach and seeded onto biodegradable scaffolds. The constructs were implanted into the omentum of adult mice. Implants were harvested at designated time points and analyzed with histology and immunohistochemistry. RESULTS Tissue-engineered stomach grows as an expanding sphere with a simple columnar epithelium organized into gastric glands and an adjacent muscularis. The regenerated gastric epithelium demonstrates differentiation of all four cell types: mucous, enteroendocrine, chief, and parietal cells. Tissue-engineered stomach epithelium proliferates at a rate comparable to native glandular stomach and expresses two putative stem cell markers: DCAMKL-1 and Lgr5. CONCLUSIONS This study demonstrates the successful generation of tissue-engineered stomach in a mouse model for the first time. Regenerated gastric epithelium is able to appropriately proliferate and differentiate. The generation of murine tissue-engineered stomach is a necessary advance as it provides the transgenic tools required to investigate the molecular and cellular mechanisms of this regenerative process. Delineating the mechanism of how tissue-engineered stomach develops in vivo is an important precursor to its use as a human stomach replacement therapy.
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Affiliation(s)
- Allison L Speer
- Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA
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Fukui T, Kishimoto M, Nakajima A, Yamashina M, Nakayama S, Kusuda T, Sakaguchi Y, Yoshida K, Uchida K, Nishio A, Matsuzaki K, Okazaki K. The specific linker phosphorylation of Smad2/3 indicates epithelial stem cells in stomach; particularly increasing in mucosae of Helicobacter-associated gastritis. J Gastroenterol 2011; 46:456-68. [PMID: 21229365 DOI: 10.1007/s00535-010-0364-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Accepted: 12/12/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND The gastric corpus and antrum are believed to contain epithelial stem cells in the isthmus. However, the lack of useful markers has hindered studies of their origin. We explored whether Smad2/3, phosphorylated at specific linker threonine residues (pSmad2/3L-Thr), could serve as a marker for stem cells. METHODS Stomachs, small intestines, and colons from Helicobacter felis-infected and noninfected C57BL/6 mice were examined. Double immunofluorescent staining of pSmad2/3L-Thr with Ki67, cytokeratin 8, or doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) was performed, and pSmad2/3L-Thr immunostaining-positive cells were counted. After immunofluorescent staining, we stained the same sections with hematoxylin-eosin and observed these cells under a light microscope. RESULTS In infected mice, pSmad2/3L-Thr immunostaining-positive cells were significantly increased in the corpus and antrum compared with those of noninfected mice (p < 0.0001). The number of Ki67 immunostaining-positive cells in the corpus and antrum of infected mice was also much greater than in the noninfected mice. Although pSmad2/3L-Thr immunostaining-positive cells were detected among the Ki67 cells, immunohistochemical co-localization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr immunostaining-positive cells showed immunohistochemical co-localization with cytokeratin 8, but some of them showed co-localization or adjacent localization with DCAMKL1 immunostaining-positive cells. Under a light microscope, pSmad2/3L-Thr immunostaining-positive cells indicated undifferentiated morphological features and were confirmed in the isthmus. In small intestines and colons, pSmad2/3L-Thr immunostaining-positive cells were detected in specific epithelial cells around crypt bases, where the respective putative stem cells are thought to exist. CONCLUSIONS We have identified the significant expression of pSmad2/3L-Thr in specific epithelial cells of the murine stomach and have suggested these cells to be epithelial stem cells.
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Affiliation(s)
- Toshiro Fukui
- The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
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Kikuchi M, Nagata H, Watanabe N, Watanabe H, Tatemichi M, Hibi T. Altered expression of a putative progenitor cell marker DCAMKL1 in the rat gastric mucosa in regeneration, metaplasia and dysplasia. BMC Gastroenterol 2010; 10:65. [PMID: 20565818 PMCID: PMC2912238 DOI: 10.1186/1471-230x-10-65] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 06/18/2010] [Indexed: 12/21/2022] Open
Abstract
Background Doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) is a candidate marker for progenitor cells in the gastrointestinal mucosa. Lineage cells in the gastric mucosa are derived from progenitor cells, but this process can be altered after injury. Therefore, we explored DCAMKL1 expression under pathological conditions. Methods An immunohistochemical analysis was performed in rat stomach with acute superficial injury, chronic ulcer, intestinal metaplasia and dysplasia. Results DCAMKL1 was exclusively expressed in immature quiescent cells in the isthmus of normal fundic glands, where putative progenitor cells are thought to reside. DCAMKL1-positive cells and proliferating cells shed into the lumen after superficial injury and re-appeared during the regenerative process, mainly in the superficial mucosa. In the marginal mucosa around the active ulcer, parietal and chief cells diminished, foveolar hyperplasia was evident, and trefoil factor family 2 (TFF2)/spasmolytic polypeptide-expressing metaplasia (SPEM) emerged at the gland base. DCAMKL1 cells re-emerged in the deep mucosa juxtaposed with SPEM and proliferating cells. In the healing ulcer, the TFF2 cell population expanded and seemed to redifferentiate to chief cells, while proliferating cells and DCAMKL1 cells appeared above and below the TFF2 cells to promote healing. SPEM appeared and PCNA cells increased in the intestinalized mucosa, and DCAMKL1 was expressed in the proximity of the PCNA cells in the deep mucosa. DCAMKL1, PCNA and TFF2 were expressed in different dysplastic cells lining dilated glands near SPEM. Conclusion The ultrastructural appearance of DCAMKL1-positive cells and the expression patterns of DCAMKL1 in normal and pathological states indicate that the cells belong to a progenitor cell population. DCAMKL1 expression is closely associated with TFF2/SPEM cells after injury. DCAMKL1 cells repopulate close to proliferating, hyperplastic, metaplastic and dysplastic cells, and the progenitor zone shifts according to the pathological circumstances.
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Affiliation(s)
- Miho Kikuchi
- Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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