Intestinal Stem Cells: Common Signal Pathways, Human Disease Correlation, and Implications for Therapies

Enterocytes originating from gastrointestinal stem cells are basic building blocks of villi and crypts in human intestine. Little is known about intestinal stem cells (ISCs), their interaction with niche, and key pathways in their regulation. In this paper, we have reviewed the characteristics of ISC, its interaction with niche, and the understanding of key signaling pathways like Wnt. A better understanding of all of this will help to better utilize novel therapies like mesenchymal stromal cells (MSCs), R-spondin1, and sulindac in various disorders like colon cancer, graft-versus-host disease, intestinal polyposis, and radiation-related bowel injuries.

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PTEN-deficient intestinal stem cells initiate intestinal polyposis

Nature Genetics ◽

10.1038/ng1928 ◽

2007 ◽

Vol 39 (2) ◽

pp. 189-198 ◽

Cited By ~ 302

Author(s):

Xi C He ◽

Tong Yin ◽

Justin C Grindley ◽

Qiang Tian ◽

Toshiro Sato ◽

...

Keyword(s):

Stem Cells ◽

Intestinal Stem Cells ◽

Intestinal Polyposis

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

Journal of Experimental Medicine ◽

10.1084/jem.20101559 ◽

2011 ◽

Vol 208 (2) ◽

pp. 285-294 ◽

Cited By ~ 83

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.

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Abstract 5931: PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo

10.1158/1538-7445.am2018-5931 ◽

2018 ◽

Author(s):

Gediminas Greicius ◽

Zahra Kabiri ◽

Kristmundur Sigmundsson ◽

Chao Liang ◽

Ralph Bunte ◽

...

Keyword(s):

Stem Cells ◽

Stromal Cells ◽

Intestinal Stem Cells

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Paneth and Intestinal Stem Cells are Differentially Affected during Worsening of Acute Cellular Rejection in Small Bowel Transplantation compared to Intestinal Ischemia Reperfusion Injury and Graft versus Host Disease

Transplantation Journal ◽

10.1097/01.tp.0000543009.38422.7d ◽

2018 ◽

Vol 102 ◽

pp. S298

Author(s):

Melisa Pucci Molinaris ◽

Virginia Gonzalez Polo ◽

Diego Ramisch ◽

Dominik Meier ◽

Martin Rumbo ◽

...

Keyword(s):

Stem Cells ◽

Intestinal Ischemia ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Small Bowel Transplantation ◽

Acute Cellular Rejection ◽

Intestinal Stem Cells ◽

Graft Versus Host ◽

Intestinal Ischemia Reperfusion ◽

Cellular Rejection

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Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

International Journal of Molecular Sciences ◽

10.3390/ijms22010357 ◽

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.

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Faculty Opinions recommendation of The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.8640956.9144054 ◽

2011 ◽

Author(s):

Philippe Saas ◽

Sylvain Perruche

Keyword(s):

Stem Cells ◽

Graft Versus Host Disease ◽

Intestinal Stem Cells ◽

Host Disease ◽

Graft Versus Host

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MRISCs protect colonic stem cells from inflammatory damage

Cell Regeneration ◽

10.1186/s13619-021-00086-4 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Guoli Zhu ◽

Rongwen Xi

Keyword(s):

Stem Cells ◽

Stromal Cells ◽

Intestinal Stem Cells ◽

Colonic Crypt ◽

Colonic Inflammation ◽

Intestinal Diseases ◽

Functional Roles ◽

Inflammatory Damage ◽

And Function ◽

Colonic Stem Cells

AbstractIncreasing evidence suggest functional roles of subepithelial mesenchymal niche cells in maintaining intestinal stem cells and in modulating the pathogenesis of various intestinal diseases in mammals. A recent study reported the discovery of a new population of stromal cells in mice termed MAP3K2-Regulated Intestinal Stromal Cells (MRISCs); these cells reside at the base of colonic crypt and function to protect colonic stem cells during colonic inflammation by expressing the Wnt agonist R-spondin1 (Rspo1).

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