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 Lgr5+ intestinal stem cells reside in an unlicensed G1 phase

2018 ◽  
Vol 217 (5) ◽  
pp. 1667-1685 ◽  
Author(s):  
Thomas D. Carroll ◽  
Ian P. Newton ◽  
Yu Chen ◽  
J. Julian Blow ◽  
Inke Näthke
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Small Intestine ◽  
Intestinal Stem Cells ◽  
G1 Phase ◽  
Temporal Window ◽  
Restriction Point ◽  
Origins Of Replication ◽  
Interphase Cells ◽  
Functional Restriction

During late mitosis and the early G1 phase, the origins of replication are licensed by binding to double hexamers of MCM2–7. In this study, we investigated how licensing and proliferative commitment are coupled in the epithelium of the small intestine. 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 the 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, characterized 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 phase of intestinal stem cells creates a temporal window when proliferative fate decisions can be made.

scholarly journals A novel in vitro survival assay of small intestinal stem cells after exposure to ionizing radiation

2014 ◽  
Vol 55 (2) ◽  
pp. 381-390 ◽  
Author(s):  
Motohiro Yamauchi ◽  
Kensuke Otsuka ◽  
Hisayoshi Kondo ◽  
Nobuyuki Hamada ◽  
Masanori Tomita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ionizing Radiation ◽  
Intestinal Stem Cells ◽  
Survival Assay ◽  
Small Intestinal ◽  
In Vitro Survival

scholarly journals Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells

2017 ◽  
Vol 31 (S1) ◽  
Author(s):  
Kunihiro Kishida ◽  
Sarah Pearce ◽  
Shiyan Yu ◽  
Nan Gao ◽  
Ronaldo Ferraris
Keyword(s):  
Stem Cells ◽  
Nutrient Sensing ◽  
Intestinal Stem Cells ◽  
Small Intestinal

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 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 Defining hierarchies of stemness in the intestine: evidence from biomarkers and regulatory pathways

2014 ◽  
Vol 307 (3) ◽  
pp. G260-G273 ◽  
Author(s):  
A. D. Gracz ◽  
S. T. Magness
Keyword(s):  
Intestinal Epithelium ◽  
Cell Biology ◽  
Biomarker Discovery ◽  
Intestinal Stem Cells ◽  
Signaling Networks ◽  
Stem Cell Biology ◽  
Regulatory Pathways ◽  
Small Intestinal Epithelium ◽  
Functional Studies ◽  
Small Intestinal

For decades, the rapid proliferation and well-defined cellular lineages of the small intestinal epithelium have driven an interest in the biology of the intestinal stem cells (ISCs) and progenitors that produce the functional cells of the epithelium. Recent and significant advances in ISC biomarker discovery have established the small intestinal epithelium as a powerful model system for studying general paradigms in somatic stem cell biology and facilitated elegant genetic and functional studies of stemness in the intestine. However, this newfound wealth of ISC biomarkers raises important questions of marker specificity. Furthermore, the ISC field must now begin to reconcile biomarker status with functional stemness, a challenge that is made more complex by emerging evidence that cellular hierarchies in the intestinal epithelium are more plastic than previously imagined, with some progenitor populations capable of dedifferentiating and functioning as ISCs following damage. In this review, we discuss the state of the ISC field in terms of biomarkers, tissue dynamics, and cellular hierarchies, and how these processes might be informed by earlier studies into signaling networks in the small intestine.

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.

ALX-0600, a glucagon-like peptide-2 analogue, protects small intestinal stem cells from radiation damage

2003 ◽  
Vol 124 (4) ◽  
pp. A609-A610 ◽  
Author(s):  
Christopher S. Potten ◽  
Sarah Williamsom ◽  
Demchyshyn Lidia L. ◽  
Catherine S. Booth
Keyword(s):  
Stem Cells ◽  
Radiation Damage ◽  
Intestinal Stem Cells ◽  
Glucagon Like Peptide ◽  
Small Intestinal

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
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