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Stem Cells in the Intestine: Possible Roles in Pathogenesis of Irritable Bowel Syndrome.

Ratanasirintrawoot S, Israsena N - J Neurogastroenterol Motil (2016)

Bottom Line: Interaction between intestinal stem cells and various signals from their environment is important for the control of stem cell self-renewal, regulation of number and function of specific intestinal cell types, and maintenance of the mucosal barrier.Besides their roles in stem cell regulation, these signals are also known to have potent effects on immune cells, enteric nervous system and secretory cells in the gut, and may be responsible for various aspects of pathogenesis of functional GI disorders, including visceral hypersensitivity, altered gut motility and low grade gut inflammation.In this article, we briefly summarize the components of these signaling pathways, how they can be modified by extrinsic factors and novel treatments, and provide evidenced support of their roles in the inflammation processes.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Cell Therapy Research Unit, Chulalongkorn University, Bangkok, Thailand.

ABSTRACT
Irritable bowel syndrome is one of the most common functional gastrointestinal (GI) disorders that significantly impair quality of life in patients. Current available treatments are still not effective and the pathophysiology of this condition remains unclearly defined. Recently, research on intestinal stem cells has greatly advanced our understanding of various GI disorders. Alterations in conserved stem cell regulatory pathways such as Notch, Wnt, and bone morphogenic protein/TGF- β have been well documented in diseases such as inflammatory bowel diseases and cancer. Interaction between intestinal stem cells and various signals from their environment is important for the control of stem cell self-renewal, regulation of number and function of specific intestinal cell types, and maintenance of the mucosal barrier. Besides their roles in stem cell regulation, these signals are also known to have potent effects on immune cells, enteric nervous system and secretory cells in the gut, and may be responsible for various aspects of pathogenesis of functional GI disorders, including visceral hypersensitivity, altered gut motility and low grade gut inflammation. In this article, we briefly summarize the components of these signaling pathways, how they can be modified by extrinsic factors and novel treatments, and provide evidenced support of their roles in the inflammation processes. Furthermore, we propose how changes in these signals may contribute to the symptom development and pathogenesis of irritable bowel syndrome.

No MeSH data available.


Related in: MedlinePlus

Signaling pathways important for stem/progenitor cells regulation. (A) Notch signaling pathway. Cell-cell interaction is required for lateral inhibition. The sending cell produces Delta which binds and activates Notch in the adjacent cell. Matrix metalloproteinases (MMPs) such as Adam10 and Adam17 proteolytically cleave Notch extracellular domain while gamma secretase cleaves intracellular domain, leading to transcriptional activation of Notch target genes which feedback to inhibit Notch in the sending cell. (B) Wnt signaling pathway. In the absence of ligand (left), β-catenin is inhibited by the destruction complex. Binding of Wnt ligand to receptors frees β-catenin which displaces the transcriptional repressor Groucho. Together with the T cell factor (TCF) transcription factor, β-catenin activates Wnt target genes including some of its own receptors. Of note, R-spondin can potentiate Wnt signaling through inhibiting ZNRF3/RNF43 which normally inhibits the Wnt transmembrane receptor Frizzled. DKK, Dickkopf.
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f2-jnm-22-367: Signaling pathways important for stem/progenitor cells regulation. (A) Notch signaling pathway. Cell-cell interaction is required for lateral inhibition. The sending cell produces Delta which binds and activates Notch in the adjacent cell. Matrix metalloproteinases (MMPs) such as Adam10 and Adam17 proteolytically cleave Notch extracellular domain while gamma secretase cleaves intracellular domain, leading to transcriptional activation of Notch target genes which feedback to inhibit Notch in the sending cell. (B) Wnt signaling pathway. In the absence of ligand (left), β-catenin is inhibited by the destruction complex. Binding of Wnt ligand to receptors frees β-catenin which displaces the transcriptional repressor Groucho. Together with the T cell factor (TCF) transcription factor, β-catenin activates Wnt target genes including some of its own receptors. Of note, R-spondin can potentiate Wnt signaling through inhibiting ZNRF3/RNF43 which normally inhibits the Wnt transmembrane receptor Frizzled. DKK, Dickkopf.

Mentions: Notch pathway signals via a direct cell-to-cell contact. In the mammalian intestine, membrane-bound Notch ligands (Dll1 and Dll4) from one cell bind to transmembrane Notch receptors on the surface of the adjacent cell to activate the signaling cascade (Fig. 2A).19,50 The extracellular portion of bound receptors is proteolytically cleaved by a disintegrin and metalloprotease (ADAM)/TNF-α converting enzyme (TACE) followed by intramembrane cleavage by gamma secretase. The active Notch intracellular domain is released and subsequently translocates into the nucleus to activate downstream targets such as Hes which represses multiple genes, including secretory fate-promoting Math1.51 Notch signaling inhibits expression of cyclin-dependent kinase p27Kip1 and p57Kip2 in intestinal progenitors therefore maintains them in a proliferating state.52


Stem Cells in the Intestine: Possible Roles in Pathogenesis of Irritable Bowel Syndrome.

Ratanasirintrawoot S, Israsena N - J Neurogastroenterol Motil (2016)

Signaling pathways important for stem/progenitor cells regulation. (A) Notch signaling pathway. Cell-cell interaction is required for lateral inhibition. The sending cell produces Delta which binds and activates Notch in the adjacent cell. Matrix metalloproteinases (MMPs) such as Adam10 and Adam17 proteolytically cleave Notch extracellular domain while gamma secretase cleaves intracellular domain, leading to transcriptional activation of Notch target genes which feedback to inhibit Notch in the sending cell. (B) Wnt signaling pathway. In the absence of ligand (left), β-catenin is inhibited by the destruction complex. Binding of Wnt ligand to receptors frees β-catenin which displaces the transcriptional repressor Groucho. Together with the T cell factor (TCF) transcription factor, β-catenin activates Wnt target genes including some of its own receptors. Of note, R-spondin can potentiate Wnt signaling through inhibiting ZNRF3/RNF43 which normally inhibits the Wnt transmembrane receptor Frizzled. DKK, Dickkopf.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4930294&req=5

f2-jnm-22-367: Signaling pathways important for stem/progenitor cells regulation. (A) Notch signaling pathway. Cell-cell interaction is required for lateral inhibition. The sending cell produces Delta which binds and activates Notch in the adjacent cell. Matrix metalloproteinases (MMPs) such as Adam10 and Adam17 proteolytically cleave Notch extracellular domain while gamma secretase cleaves intracellular domain, leading to transcriptional activation of Notch target genes which feedback to inhibit Notch in the sending cell. (B) Wnt signaling pathway. In the absence of ligand (left), β-catenin is inhibited by the destruction complex. Binding of Wnt ligand to receptors frees β-catenin which displaces the transcriptional repressor Groucho. Together with the T cell factor (TCF) transcription factor, β-catenin activates Wnt target genes including some of its own receptors. Of note, R-spondin can potentiate Wnt signaling through inhibiting ZNRF3/RNF43 which normally inhibits the Wnt transmembrane receptor Frizzled. DKK, Dickkopf.
Mentions: Notch pathway signals via a direct cell-to-cell contact. In the mammalian intestine, membrane-bound Notch ligands (Dll1 and Dll4) from one cell bind to transmembrane Notch receptors on the surface of the adjacent cell to activate the signaling cascade (Fig. 2A).19,50 The extracellular portion of bound receptors is proteolytically cleaved by a disintegrin and metalloprotease (ADAM)/TNF-α converting enzyme (TACE) followed by intramembrane cleavage by gamma secretase. The active Notch intracellular domain is released and subsequently translocates into the nucleus to activate downstream targets such as Hes which represses multiple genes, including secretory fate-promoting Math1.51 Notch signaling inhibits expression of cyclin-dependent kinase p27Kip1 and p57Kip2 in intestinal progenitors therefore maintains them in a proliferating state.52

Bottom Line: Interaction between intestinal stem cells and various signals from their environment is important for the control of stem cell self-renewal, regulation of number and function of specific intestinal cell types, and maintenance of the mucosal barrier.Besides their roles in stem cell regulation, these signals are also known to have potent effects on immune cells, enteric nervous system and secretory cells in the gut, and may be responsible for various aspects of pathogenesis of functional GI disorders, including visceral hypersensitivity, altered gut motility and low grade gut inflammation.In this article, we briefly summarize the components of these signaling pathways, how they can be modified by extrinsic factors and novel treatments, and provide evidenced support of their roles in the inflammation processes.

View Article: PubMed Central - PubMed

Affiliation: Stem Cell and Cell Therapy Research Unit, Chulalongkorn University, Bangkok, Thailand.

ABSTRACT
Irritable bowel syndrome is one of the most common functional gastrointestinal (GI) disorders that significantly impair quality of life in patients. Current available treatments are still not effective and the pathophysiology of this condition remains unclearly defined. Recently, research on intestinal stem cells has greatly advanced our understanding of various GI disorders. Alterations in conserved stem cell regulatory pathways such as Notch, Wnt, and bone morphogenic protein/TGF- β have been well documented in diseases such as inflammatory bowel diseases and cancer. Interaction between intestinal stem cells and various signals from their environment is important for the control of stem cell self-renewal, regulation of number and function of specific intestinal cell types, and maintenance of the mucosal barrier. Besides their roles in stem cell regulation, these signals are also known to have potent effects on immune cells, enteric nervous system and secretory cells in the gut, and may be responsible for various aspects of pathogenesis of functional GI disorders, including visceral hypersensitivity, altered gut motility and low grade gut inflammation. In this article, we briefly summarize the components of these signaling pathways, how they can be modified by extrinsic factors and novel treatments, and provide evidenced support of their roles in the inflammation processes. Furthermore, we propose how changes in these signals may contribute to the symptom development and pathogenesis of irritable bowel syndrome.

No MeSH data available.


Related in: MedlinePlus