scholarly journals The Hippo–YAP Signaling as Guardian in the Pool of Intestinal Stem Cells

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 560
Author(s):  
Yoojin Seo ◽  
So-Yeon Park ◽  
Hyung-Sik Kim ◽  
Jeong-Seok Nam
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelium ◽  
Fine Tuning ◽  
Intestinal Stem Cells ◽  
Dynamic Regulation ◽  
Intestinal Integrity ◽  
Differentiated Cells ◽  
Quiescent Stem Cells ◽  
G Protein Coupled ◽  
Crypt Base

Despite endogenous insults such as mechanical stress and danger signals derived from the microbiome, the intestine can maintain its homeostatic condition through continuous self-renewal of the crypt–villus axis. This extraordinarily rapid turnover of intestinal epithelium, known to be 3 to 5 days, can be achieved by dynamic regulation of intestinal stem cells (ISCs). The crypt base-located leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) ISCs maintain intestinal integrity in the steady state. Under severe damage leading to the loss of conventional ISCs, quiescent stem cells and even differentiated cells can be reactivated into stem-cell-like cells with multi-potency and contribute to the reconstruction of the intestinal epithelium. This process requires fine-tuning of the various signaling pathways, including the Hippo–YAP system. In this review, we summarize recent advances in understanding the correlation between Hippo–YAP signaling and intestinal homeostasis, repair, and tumorigenesis, focusing specifically on ISC regulation.

scholarly journals Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

2020 ◽  
Vol 22 (1) ◽  
pp. 357
Author(s):  
Ken Kurokawa ◽  
Yoku Hayakawa ◽  
Kazuhiko Koike
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Inflammatory Cytokines ◽  
Intestinal Epithelium ◽  
Intestinal Stem Cells ◽  
Signal Pathways ◽  
Epithelial Regeneration ◽  
Cell Functions ◽  
Differentiated Cells ◽  
Stem Cell Niches

The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration.

scholarly journals Rapidly cycling stem cells regenerate the intestine independent of Lgr5high cells

2019 ◽  
Author(s):  
Xiaole Sheng ◽  
Ziguang Lin ◽  
Cong Lv ◽  
Chunlei Shao ◽  
Xueyun Bi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Single Cell ◽  
Intestinal Epithelium ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
Damage Resistance ◽  
Single Cell Rna Sequencing ◽  
Radiation Repair ◽  
Crypt Base

AbstractThe +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1+) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1+ cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1+ cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1+ cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1+ cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.

scholarly journals Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue

2008 ◽  
Vol 8 ◽  
pp. 1168-1176 ◽  
Author(s):  
Laren Becker ◽  
Qin Huang ◽  
Hiroshi Mashimo
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Niche ◽  
Intestinal Stem Cells ◽  
Stem Cell Marker ◽  
Tumor Initiating Cells ◽  
Colonic Adenomas ◽  
Potential Marker ◽  
Cell Niche ◽  
Crypt Base

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

scholarly journals The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells

2011 ◽  
Vol 208 (2) ◽  
pp. 285-294 ◽  
Author(s):  
Shuichiro Takashima ◽  
Masanori Kadowaki ◽  
Kazutoshi Aoyama ◽  
Motoko Koyama ◽  
Takeshi Oshima ◽  
...  
Keyword(s):  
Stem Cells ◽  
Graft Versus Host Disease ◽  
Intestinal Epithelium ◽  
Critical Role ◽  
Intestinal Stem Cells ◽  
Allogeneic Bone ◽  
Gi Tract ◽  
Host Disease ◽  
Graft Versus Host ◽  
Allogeneic Bmt

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.

scholarly journals Wnt/β-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells

2007 ◽  
Vol 27 (21) ◽  
pp. 7551-7559 ◽  
Author(s):  
Tea Fevr ◽  
Sylvie Robine ◽  
Daniel Louvard ◽  
Joerg Huelsken
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Intestinal Epithelium ◽  
Transcriptional Profiling ◽  
Wnt Signaling Pathway ◽  
Intestinal Stem Cells ◽  
Intestinal Homeostasis ◽  
Adult Mice ◽  
Gene Ablation ◽  
Functional Preservation

ABSTRACT The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible β-catenin gene ablation in adult mice. Block of Wnt/β-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of β-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/β-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.

scholarly journals Tissue underlying the intestinal epithelium elicits proliferation of intestinal stem cells following cytotoxic damage

2015 ◽  
Vol 361 (2) ◽  
pp. 427-438 ◽  
Author(s):  
Kristen M Seiler ◽  
Erica L Schenhals ◽  
Richard J von Furstenberg ◽  
Bhavya K Allena ◽  
Brian J Smith ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelium ◽  
Intestinal Stem Cells

302 Dynamic Regulation of Intestinal Crypt Base Columnar Stem Cells by Notch Signaling

2012 ◽  
Vol 142 (5) ◽  
pp. S-68
Author(s):  
Alexis J. Carulli ◽  
Gail B. Gifford ◽  
Wenli Liu ◽  
Linda C. Samuelson
Keyword(s):  
Stem Cells ◽  
Notch Signaling ◽  
Dynamic Regulation ◽  
Intestinal Crypt ◽  
Crypt Base

scholarly journals Delayed activation of the DNA replication licensing system in Lgr5(+) intestinal stem cells

2017 ◽  
Author(s):  
T.D. Carroll ◽  
I.P. Newton ◽  
Y. Chen ◽  
J.J. Blow ◽  
I. Näthke
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Replication ◽  
Intestinal Epithelium ◽  
Intestinal Stem Cells ◽  
Temporal Window ◽  
Restriction Point ◽  
Interphase Cells ◽  
Small Intestinal ◽  
Functional Restriction

ABSTRACTDuring late mitosis and early G1, replication origins are licensed for replication by binding to double hexamers of MCM2-7. Here, we investigate how licensing and proliferative commitment are coupled in the small-intestinal epithelium. We developed a method for identifying cells in intact tissue containing DNA-bound MCM2-7. Interphase cells above the transit-amplifying compartment had no DNA-bound MCM2-7, but still expressed MCM2-7 protein, suggesting that licensing is inhibited immediately upon differentiation. Strikingly, we found most proliferative Lgr5(+) stem cells are in an unlicensed state. This suggests that the elongated cell-cycle of intestinal stem-cells is caused by an increased G1 length, characterised by dormant periods with unlicensed origins. Significantly, the unlicensed state is lost In Apc mutant epithelium, which lacks a functional restriction point, causing licensing immediately upon G1 entry. We propose that the unlicensed G1 of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

scholarly journals DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions

2013 ◽  
Vol 33 (9) ◽  
pp. 1735-1745 ◽  
Author(s):  
Li-Lun Ho ◽  
Amit Sinha ◽  
Michael Verzi ◽  
Kathrin M. Bernt ◽  
Scott A. Armstrong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Intestinal Epithelium ◽  
Target Genes ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Aberrant Expression ◽  
Genome Wide ◽  
Transcript Profiles ◽  
H3k79 Methylation

Methylation of H3K79 is associated with chromatin at expressed genes, though it is unclear if this histone modification is required for transcription of all genes. Recent studies suggest that Wnt-responsive genes depend particularly on H3K79 methylation, which is catalyzed by the methyltransferase DOT1L. Human leukemias carrying MLL gene rearrangements show DOT1L-mediated H3K79 methylation and aberrant expression of leukemogenic genes. DOT1L inhibitors reverse these effects, but their clinical use is potentially limited by toxicity in Wnt-dependent tissues such as intestinal epithelium. Genome-wide positioning of the H3K79me2 mark in Lgr5 + mouse intestinal stem cells and mature intestinal villus epithelium correlated with expression levels of all transcripts and not with Wnt-responsive genes per se . Selective Dot1l disruption in Lgr5 + stem cells or in whole intestinal epithelium eliminated H3K79me2 from the respective compartments, allowing genetic evaluation of DOT1L requirements. The absence of methylated H3K79 did not impair health, intestinal homeostasis, or expression of Wnt target genes in crypt epithelium for up to 4 months, despite increased crypt cell apoptosis. Global transcript profiles in Dot1l -null cells were barely altered. Thus, H3K79 methylation is not essential for transcription of Wnt-responsive or other intestinal genes, and intestinal toxicity is not imperative when DOT1L is rendered inactive in vivo .

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