Notch as a Driver of Gastric Epithelial Cell Proliferation
2017; Elsevier BV; Volume: 3; Issue: 3 Linguagem: Inglês
10.1016/j.jcmgh.2017.01.012
ISSN2352-345X
AutoresElise S. Demitrack, Linda C. Samuelson,
Tópico(s)Cancer-related gene regulation
ResumoThe gastric epithelium is sustained by a population of stem cells that replenish the various mature epithelial lineages throughout adulthood. Regulation of stem and progenitor cell proliferation occurs via basic developmental signaling pathways, including the Notch pathway, which recently was described to promote gastric stem cell proliferation in both mice and human beings. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth, and that basic signaling pathways, such as Notch, which stimulate stem cell proliferation, can promote tumorigenesis. Accordingly, constitutive Notch activation leads to unchecked cellular proliferation and gastric tumors in genetic mouse models. Furthermore, there is emerging evidence suggesting that the Notch pathway may be activated in some human gastric cancers, supporting a potential role for Notch in gastric tumorigenesis. In this review, we first summarize the current understanding of gastric stem cells defined by genetic mouse studies, followed by discussion of the literature regarding Notch pathway regulation of gastric stem cell function in the mouse and human beings. Notch action to maintain gastric epithelial cell homeostasis and the cellular consequences of dysregulated signaling to promote tumorigenesis are discussed, including studies associating Notch activation with human gastric cancer. Finally, we compare and contrast Notch function in the stomach with other gastrointestinal tissues, including the intestine, to highlight the sensitivity of the stomach to Notch-induced tumors. The gastric epithelium is sustained by a population of stem cells that replenish the various mature epithelial lineages throughout adulthood. Regulation of stem and progenitor cell proliferation occurs via basic developmental signaling pathways, including the Notch pathway, which recently was described to promote gastric stem cell proliferation in both mice and human beings. Current cancer theory proposes that adult stem cells that maintain gastrointestinal tissues accumulate mutations that promote cancerous growth, and that basic signaling pathways, such as Notch, which stimulate stem cell proliferation, can promote tumorigenesis. Accordingly, constitutive Notch activation leads to unchecked cellular proliferation and gastric tumors in genetic mouse models. Furthermore, there is emerging evidence suggesting that the Notch pathway may be activated in some human gastric cancers, supporting a potential role for Notch in gastric tumorigenesis. In this review, we first summarize the current understanding of gastric stem cells defined by genetic mouse studies, followed by discussion of the literature regarding Notch pathway regulation of gastric stem cell function in the mouse and human beings. Notch action to maintain gastric epithelial cell homeostasis and the cellular consequences of dysregulated signaling to promote tumorigenesis are discussed, including studies associating Notch activation with human gastric cancer. Finally, we compare and contrast Notch function in the stomach with other gastrointestinal tissues, including the intestine, to highlight the sensitivity of the stomach to Notch-induced tumors. SummaryThe Notch signaling pathway has emerged as a critical regulator of gastric stem cell homeostasis in both mouse and human stomachs. Notch promotes gastric stem/progenitor cell proliferation via activation of the NOTCH1 and NOTCH2 receptors. Accordingly, constitutive Notch activation activates gastric stem cells, resulting in gland fission, tissue expansion, and tumor formation. The Notch signaling pathway has emerged as a critical regulator of gastric stem cell homeostasis in both mouse and human stomachs. Notch promotes gastric stem/progenitor cell proliferation via activation of the NOTCH1 and NOTCH2 receptors. Accordingly, constitutive Notch activation activates gastric stem cells, resulting in gland fission, tissue expansion, and tumor formation. Gastric cancer (GC) is a significant human health problem. Worldwide, it is the fifth most common cancer and the third leading cause of cancer-related deaths.1Torre L.A. Bray F. Siegel R.L. et al.Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Crossref PubMed Scopus (23652) Google Scholar Despite a recent decrease in incidence in the United States, GC remains a serious burden, with the National Cancer Institute estimating 26,000 new cases and 11,000 deaths in 2016. There are few effective treatment options for GC and only 30% of patients will survive for 5 years or more. The recent genetic profiling of almost 300 human gastric adenocarcinomas in The Cancer Genome Atlas identified 4 molecular GC subgroups: Epstein–Barr virus positive, microsatellite instability, genome stable, and chromosomal instability.2Cancer Genome Atlas Research NetworkComprehensive molecular characterization of gastric adenocarcinoma.Nature. 2014; 513: 202-209Crossref PubMed Scopus (3948) Google Scholar Each subtype was associated with a distinct molecular signature, providing valuable molecular clues that can help to uncover drivers of tumorigenesis and identify potential therapeutic targets. A complementary approach to molecular profiling of human gastric cancers is to decipher the key signaling pathways that promote gastric stem/progenitor cell proliferation during homeostasis. Basic developmental signaling pathways that regulate stem cell homeostasis can be key drivers of tumorigenesis in gastrointestinal (GI) tissues. For example, Wnt pathway signaling is required to maintain intestinal stem cells and Wnt-activating mutations are observed in more than 80% of colorectal cancers, primarily via mutation of the Wnt negative regulator APC.3Huels D.J. Sansom O.J. Stem vs non-stem cell origin of colorectal cancer.Br J Cancer. 2015; 113: 1-5Crossref PubMed Scopus (57) Google Scholar Current theory is that Wnt-activating mutations accumulate in intestinal stem cells to initiate and maintain tumors.4Vries R.G. Huch M. Clevers H. Stem cells and cancer of the stomach and intestine.Mol Oncol. 2010; 4: 373-384Crossref PubMed Scopus (91) Google Scholar A similar unifying tumor-driving pathway required to maintain gastric stem cells has not been identified in stomach, perhaps because of the variability between GC subtypes as well as a comparatively rudimentary understanding of gastric stem cells. The identification of gastric stem cells in mouse models has set the stage to define the niche factors regulating these cells and thereby potential pathways driving gastric cancer cell proliferation. In this review we summarize studies that have shown a key role for the Notch signaling pathway to maintain gastric stem cells. Notch function in both the corpus and antral regions of the stomach are presented from analysis of mouse models, and mouse and human gastric organoids. The studies have shown that Notch functions to promote stem/progenitor cell proliferation in the stomach. Accordingly, constitutive Notch activation in gastric stem cells was shown to induce gastric tumors in mouse.5Demitrack E.S. Gifford G.B. Keeley T.M. et al.Notch signaling regulates gastric antral LGR5 stem cell function.EMBO J. 2015; 34: 2522-2536Crossref PubMed Scopus (64) Google Scholar, 6Kim T.H. Shivdasani R.A. Notch signaling in stomach epithelial stem cell homeostasis.J Exp Med. 2011; 208: 677-688Crossref PubMed Scopus (79) Google Scholar Moreover, there is emerging evidence of Notch pathway activation in some human gastric cancers.7Bauer L. Takacs A. Slotta-Huspenina J. et al.Clinical significance of NOTCH1 and NOTCH2 expression in gastric carcinomas: an immunohistochemical study.Front Oncol. 2015; 5: 94Crossref PubMed Scopus (23) Google Scholar, 8Hsu K.W. Hsieh R.H. Huang K.H. et al.Activation of the Notch1/STAT3/Twist signaling axis promotes gastric cancer progression.Carcinogenesis. 2012; 33: 1459-1467Crossref PubMed Scopus (103) Google Scholar, 9Kim S.J. Lee H.W. Baek J.H. et al.Activation of nuclear PTEN by inhibition of Notch signaling induces G2/M cell cycle arrest in gastric cancer.Oncogene. 2016; 35: 251-260Crossref PubMed Scopus (66) Google Scholar, 10Li L.C. Peng Y. Liu Y.M. et al.Gastric cancer cell growth and epithelial-mesenchymal transition are inhibited by gamma-secretase inhibitor DAPT.Oncol Lett. 2014; 7: 2160-2164Crossref PubMed Scopus (37) Google Scholar, 11Piazzi G. Fini L. Selgrad M. et al.Epigenetic regulation of delta-like1 controls Notch1 activation in gastric cancer.Oncotarget. 2011; 2: 1291-1301Crossref PubMed Scopus (56) Google Scholar, 12Yeh T.S. Wu C.W. Hsu K.W. et al.The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2.Cancer Res. 2009; 69: 5039-5048Crossref PubMed Scopus (153) Google Scholar Hence, the Notch pathway may promote both normal and cancer cell proliferation in the stomach and thus it might provide potential therapeutic targets for treatment of GC. The Notch pathway regulates key cellular processes such as proliferation and differentiation through communication between adjacent cells.13Bray S.J. Notch signalling in context.Nat Rev Mol Cell Biol. 2016; 17: 722-735Crossref PubMed Scopus (563) Google Scholar Notch components are expressed broadly to regulate many homeostatic processes in adult tissues, including the GI tract.14Demitrack E.S. Samuelson L.C. Notch regulation of gastrointestinal stem cells.J Physiol. 2016; 594: 4791-4803Crossref PubMed Scopus (78) Google Scholar The Notch signaling pathway, present in all metazoans, is highly conserved. In mammals, there are 4 Notch receptors (NOTCH1–4) and 5 Notch ligands (Delta-like 1, 3, 4, and Jagged 1 and 2), all of which are single-pass transmembrane proteins.15Kopan R. Ilagan M.X. The canonical Notch signaling pathway: unfolding the activation mechanism.Cell. 2009; 137: 216-233Abstract Full Text Full Text PDF PubMed Scopus (2564) Google Scholar The signal-sending cells express Notch ligand and the signal-receiving cells express Notch receptor. Engagement of ligand and receptor initiates proteolytic cleavage events at the cell membrane to release an intracellular signaling fragment of the Notch receptor: Notch receptor intracellular domain (NICD). In the intestine, the initial Notch receptor cleavage is performed by the membrane-localized sheddase a disintegrin and metalloproteinase 10 (ADAM10) to cleave the receptor ectodomain.16Tsai Y.H. VanDussen K.L. Sawey E.T. et al.ADAM10 regulates Notch function in intestinal stem cells of mice.Gastroenterology. 2014; 147: 822-834 e13Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar ADAM10 function in the stomach has not yet been tested. After this receptor cleavage event by ADAM10, the NICD signaling fragment is released via intramembrane cleavage by the γ-secretase complex. Subsequently, NICD translocates to the nucleus and assembles a transcription activation complex with the DNA binding protein RBP-Jκ (also known as CSL) and coactivators, including MAML, to induce the transcription of target genes such as those in the hairy and enhancer of split (Hes)-related gene family. Direct gene targets vary with tissue context, with data suggesting that Hes1 and Olfm4 may be direct Notch target genes in stomach and intestine.5Demitrack E.S. Gifford G.B. Keeley T.M. et al.Notch signaling regulates gastric antral LGR5 stem cell function.EMBO J. 2015; 34: 2522-2536Crossref PubMed Scopus (64) Google Scholar, 17VanDussen K.L. Carulli A.J. Keeley T.M. et al.Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells.Development. 2012; 139: 488-497Crossref PubMed Scopus (373) Google Scholar As a consequence of the requirement for interactions between juxtaposed cells, Notch signaling communicates short-range signals. Furthermore, the signal is short-lived, with receptor destruction an integral aspect of the signaling process, and rapid degradation of NICD resulting from its PEST domain.15Kopan R. Ilagan M.X. The canonical Notch signaling pathway: unfolding the activation mechanism.Cell. 2009; 137: 216-233Abstract Full Text Full Text PDF PubMed Scopus (2564) Google Scholar Thus, Notch signaling is well suited as a niche pathway to regulate stem cell behavior in GI tissues. The adult glandular stomach contains 2 regions: the corpus, whose primary function is the luminal secretion of acid and digestive enzymes, and the more distal antrum, which secretes the hormone gastrin. Distinct pools of actively cycling stem cells in each region fuel epithelial cell turnover throughout life. These active stem cells generate proliferating progenitors that differentiate into the various mature epithelial cell lineages of the stomach.14Demitrack E.S. Samuelson L.C. Notch regulation of gastrointestinal stem cells.J Physiol. 2016; 594: 4791-4803Crossref PubMed Scopus (78) Google Scholar In the corpus, adult stem cells thought to be located in the midregion of each gland generate progeny that migrate bidirectionally to form the differentiated cell types, including short-lived surface mucous cells, and longer-lived acid-secreting parietal cells, endocrine cells, and zymogenic lineage cells. In contrast, antral stem cells are located at the gland base and generate surface mucous cells, endocrine cells, including gastrin-producing G cells, and deep mucous cells. In general, cellular turnover is more rapid in the antrum than in the corpus, with a time frame of several days vs several weeks or months (reviewed by Mills and Shivdasani18Mills J.C. Shivdasani R.A. Gastric epithelial stem cells.Gastroenterology. 2011; 140: 412-424Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Long-term lineage tracing in genetic mouse models has been the gold standard approach for identifying stem cells in the GI tract. With this approach, genetic markers have been shown to define gastric stem cells that generate all of the differentiated epithelial cell lineages, although discovery in the stomach has lagged well behind parallel studies in the intestine. After the discovery of LGR5 as a marker for intestinal stem cells,19Barker N. van Es J.H. Kuipers J. et al.Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (3966) Google Scholar stem cells in the gastric antrum also were shown to express LGR5 by observation of lineage traces in Lgr5-EGFP-ires-CreERT2 mice more than 20 months after Cre activation with tamoxifen (TX)20Barker N. Huch M. Kujala P. et al.Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1118) Google Scholar (Table 1). In addition, single Lgr5-GFP+ antral cells isolated from this mouse strain were capable of initiating organoids with the potential to differentiate into mature gastric epithelial cell types, further supporting the conclusion that LGR5 marks an active antral stem cell. Interestingly, Lgr5-GFP cells isolated from stomach or intestine are both capable of forming long-lived organoid lines, although they each retain regional memory to form gastric or intestinal cell types despite growth under similar culture conditions.20Barker N. Huch M. Kujala P. et al.Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1118) Google Scholar, 21Sato T. Vries R.G. Snippert H.J. et al.Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (4148) Google Scholar This finding suggests that GI tract stem cells are epigenetically marked to follow prescribed region-specific differentiation programs to generate mature epithelial cells.Table 1Genetic Mouse Strains Expressed in Adult Gastric Stem CellsStrain nameActive stem cell?Induced stem cell?Differentiated cells?ReferenceAntrumCorpusAntrumCorpusLgr5-EGFP-ires-CreERT2YesNo--NoBarker et al20Barker N. Huch M. Kujala P. et al.Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1118) Google ScholarCCK2R-CreERTYesNo--Yes (corpus)Hayakawa et al25Hayakawa Y. Jin G. Wang H. et al.CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.Gut. 2015; 64: 544-553Crossref PubMed Scopus (80) Google ScholarSox2-CreERYesYes--YesArnold et al23Arnold K. Sarkar A. Yram M.A. et al.Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice.Cell Stem Cell. 2011; 9: 317-329Abstract Full Text Full Text PDF PubMed Scopus (534) Google ScholarLrig1-CreERT2YesYes--YesPowell et al24Powell A.E. Wang Y. Li Y. et al.The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.Cell. 2012; 149: 146-158Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar and Samuelson, unpublished dataeR1-CreERT2YesYes--YesMatsuo et al26Matsuo J. Kimura S. Yamamura A. et al.Identification of stem cells in the epithelium of the stomach corpus and antrum of mice.Gastroenterology. 2017; 152: 218-231Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar12.4KVil-CreNoNoYesNoNoQiao et al28Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (125) Google ScholarTroy-eGFP-ires-CreERT2NoNoaOccasional slowly expanding lineage stripes appear to originate from differentiated chief cells, with accelerated expansion after loss of active stem/progenitor cells (Stange et al29).NoYesaOccasional slowly expanding lineage stripes appear to originate from differentiated chief cells, with accelerated expansion after loss of active stem/progenitor cells (Stange et al29).YesStange et al29Stange D.E. Koo B.K. Huch M. et al.Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google ScholarMist1-CreERT2NoNo,aOccasional slowly expanding lineage stripes appear to originate from differentiated chief cells, with accelerated expansion after loss of active stem/progenitor cells (Stange et al29).yesbLineage stripes appear to originate from the isthmus region from slowly cycling cells, with accelerated expansion after loss of active stem/progenitor cells (Hayakawa et al30).NoYesaOccasional slowly expanding lineage stripes appear to originate from differentiated chief cells, with accelerated expansion after loss of active stem/progenitor cells (Stange et al29).,bLineage stripes appear to originate from the isthmus region from slowly cycling cells, with accelerated expansion after loss of active stem/progenitor cells (Hayakawa et al30).YesHayakawa et al30Hayakawa Y. Ariyama H. Stancikova J. et al.Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar and Stange et al29Stange D.E. Koo B.K. Huch M. et al.Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google ScholarNOTE. Mouse Cre drivers expressed in gastric stem cells are categorized based on their contribution to normal homeostasis (active stem cell) or in response to injury (induced stem cell). Some Cre drivers also are expressed in gastric differentiated cell types.a Occasional slowly expanding lineage stripes appear to originate from differentiated chief cells, with accelerated expansion after loss of active stem/progenitor cells (Stange et al29Stange D.E. Koo B.K. Huch M. et al.Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar).b Lineage stripes appear to originate from the isthmus region from slowly cycling cells, with accelerated expansion after loss of active stem/progenitor cells (Hayakawa et al30Hayakawa Y. Ariyama H. Stancikova J. et al.Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar). Open table in a new tab NOTE. Mouse Cre drivers expressed in gastric stem cells are categorized based on their contribution to normal homeostasis (active stem cell) or in response to injury (induced stem cell). Some Cre drivers also are expressed in gastric differentiated cell types. Unfortunately, a specific marker for the active stem cell in the adult corpus region of the stomach has not yet been described. In contrast to the antrum, Lgr5-EGFP-ires-CreERT2 does not mark active corpus stem cells; however, it does mark progenitors in the immature neonatal stomach that form adult corpus stem cells.20Barker N. Huch M. Kujala P. et al.Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1118) Google Scholar Thus, the corpus stands apart from more distal regions of the GI tract in regard to expression of Lgr5. Recently, it was shown that the Wnt signaling pathway drives gastric corpus patterning during mouse stomach development, and that Wnt activation in cultured human pluripotent stem cells induces differentiation into corpus epithelial cell types,22McCracken K.W. Aihara E. Martin B. et al.Wnt/beta-catenin promotes gastric fundus specification in mice and humans.Nature. 2017; 541: 182-187Crossref PubMed Scopus (133) Google Scholar an important finding that will further our understanding of pathway regulation of adult gastric corpus stem cells. In addition to specific stem cell markers, mouse genetic alleles have been described that are expressed in differentiated gastric cell types as well as in active stem cells. Although not specific to stem cells, these Cre drivers still can be useful tools to manipulate stem cell function because they have been observed to generate long-term lineage stripes after Cre activation (Table 1). These strains include Sox2-CreER,23Arnold K. Sarkar A. Yram M.A. et al.Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice.Cell Stem Cell. 2011; 9: 317-329Abstract Full Text Full Text PDF PubMed Scopus (534) Google Scholar Lrig1-CreERT2,24Powell A.E. Wang Y. Li Y. et al.The pan-ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor.Cell. 2012; 149: 146-158Abstract Full Text Full Text PDF PubMed Scopus (508) Google Scholar CCK2R-CreERT,25Hayakawa Y. Jin G. Wang H. et al.CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.Gut. 2015; 64: 544-553Crossref PubMed Scopus (80) Google Scholar and eR1-CreERT226Matsuo J. Kimura S. Yamamura A. et al.Identification of stem cells in the epithelium of the stomach corpus and antrum of mice.Gastroenterology. 2017; 152: 218-231Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar (Table 1). The Sox2 allele is particularly useful because it is expressed in both corpus and antral stem cells, but it is not expressed in the intestine. This is hugely advantageous for studying pathway regulation of gastric stem cells because it will allow genetic manipulation of the stomach without affecting the intestine, where changes to stem cell function can limit animal viability. One consideration is that most of the genetic mouse strains that have been identified to mark gastric stem cells have not been studied extensively, so the general utility of an individual strain is uncertain. Cellular plasticity is a hallmark of GI tissues, where cellular reprogramming has been suggested to allow committed progenitors or even mature cells to serve as reserve stem cells when active stem cells are compromised.27Mills J.C. Sansom O.J. Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract.Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar The existence of dedicated quiescent, or reserve, stem cell populations in the stomach has not been established definitively. However, certain populations of nonproliferating gastric epithelial cells have been shown to expand during tissue injury and show active stem cell lineage tracing activity. These include rare quiescent antral stem cells that express a Villin-Cre driver,28Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar and a small population of differentiated corpus chief cells expressing Troy-29Stange D.E. Koo B.K. Huch M. et al.Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar and Mist1-Cre drivers29Stange D.E. Koo B.K. Huch M. et al.Differentiated Troy+ chief cells act as reserve stem cells to generate all lineages of the stomach epithelium.Cell. 2013; 155: 357-368Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 30Hayakawa Y. Ariyama H. Stancikova J. et al.Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar (Table 1). One of these studies reported that Mist1-CreERT2 also is expressed in rare quiescent stem cells in the isthmus of corpus glands that can serve as the cell-of-origin for gastric cancer in mouse models.30Hayakawa Y. Ariyama H. Stancikova J. et al.Mist1 expressing gastric stem cells maintain the normal and neoplastic gastric epithelium and are supported by a perivascular stem cell niche.Cancer Cell. 2015; 28: 800-814Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar Furthermore, recent studies have reported that CCK2R-CreERT–expressing antral stem cells expand in response to gastrin,25Hayakawa Y. Jin G. Wang H. et al.CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.Gut. 2015; 64: 544-553Crossref PubMed Scopus (80) Google Scholar and that LGR5+ antral stem cells can expand in response to Helicobacter infection.31Sigal M. Rothenberg M.E. Logan C.Y. et al.Helicobacter pylori activates and expands Lgr5(+) stem cells through direct colonization of the gastric glands.Gastroenterology. 2015; 148: 1392-1404 e21Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar One major challenge for stem cell studies in the stomach is the extensive gastric cell toxicity observed in genetic models using TX-regulated Cre drivers. TX targets the parietal cells, inducing rapid cell death, with increased corpus progenitor cell proliferation and metaplasia following cell death. These cellular changes are transient and normal cellular homeostasis returns within 3 weeks.32Huh W.J. Khurana S.S. Geahlen J.H. et al.Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach.Gastroenterology. 2012; 142: 21-24 e7Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar Parietal cells are well known to be lynchpins in the stomach, required for corpus epithelial cell homeostasis and maintenance of the zymogenic cells in the gland base.27Mills J.C. Sansom O.J. Reserve stem cells: differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract.Sci Signal. 2015; 8: re8Crossref PubMed Scopus (95) Google Scholar Almost all of the genetic alleles that have been described to manipulate gastric stem cells in the mouse are TX-regulated Cre drivers (Table 1). The TX-induced parietal cell damage is dose-dependent,32Huh W.J. Khurana S.S. Geahlen J.H. et al.Tamoxifen induces rapid, reversible atrophy, and metaplasia in mouse stomach.Gastroenterology. 2012; 142: 21-24 e7Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar and in many instances the observed lineage traces reported for many of the gastric Cre drivers used doses that would be expected to induce parietal cell damage. Thus, there is likely to be an injury component to the response that needs to be considered. To avoid parietal cell injury, new genetic tools are needed that do not rely on acute TX treatment to manipulate genes in gastric stem cells. Notch recently was established as a crucial pathway regulating gastric stem cell proliferation and differentiation. In the fetal mouse stomach, Notch pathway components Notch1 and Jag2, and the Notch target gene Hes1, have been mapped to the nascent gastric epithelium.6Kim T.H. Shivdasani R.A. Notch signaling in stomach epithelial stem cell homeostasis.J Exp Med. 2011; 208: 677-688Crossref PubMed Scopus (79) Google Scholar Analysis of Hes1 mutant mice showed that the Notch pathway regulates cellular differentiation in the developing stomach, with excessive endocrine cell differentiation observed in perinatal mice.33Jensen J. Pedersen E.E. Galante P. et al.Control of endodermal endocrine development by Hes-1.Nat Genet. 2000; 24: 36-44Crossref PubMed Scopus (950) Google Scho
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