scholarly journals Mature enteroendocrine cells contribute to basal and pathological stem cell dynamics in the small intestine

2018 ◽  
Vol 315 (4) ◽  
pp. G495-G510 ◽  
Author(s):  
Yoshitatsu Sei ◽  
Jianying Feng ◽  
Leigh Samsel ◽  
Ayla White ◽  
Xilin Zhao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Intestinal Epithelium ◽  
Lineage Tracing ◽  
Enteroendocrine Cells ◽  
Intestinal Stem Cells ◽  
Intestinal Tumors ◽  
Cell Dynamics ◽  
Neutral Drift ◽  
Rapid Generation

Lgr5-expressing intestinal stem cells (ISCs) maintain continuous and rapid generation of the intestinal epithelium. Here, we present evidence that dedifferentiation of committed enteroendocrine cells (EECs) contributes to maintenance of the epithelium under both basal conditions and in response to injury. Lineage-tracing studies identified a subset of EECs that reside at +4 position for more than 2 wk, most of which were BrdU-label-retaining cells. Under basal conditions, cells derived from these EECs grow from the bottom of the crypt to generate intestinal epithelium according to neutral drift kinetics that is consistent with dedifferentiation of mature EECs to ISCs. The lineage tracing of EECs demonstrated reserve stem cell properties in response to radiation-induced injury with the generation of reparative EEC-derived epithelial patches. Finally, the enterochromaffin (EC) cell was the predominant EEC type participating in these stem cell dynamics. These results provide novel insights into the +4 reserve ISC hypothesis, stem cell dynamics of the intestinal epithelium, and in the development of EC-derived small intestinal tumors. NEW & NOTEWORTHY The current manuscript demonstrating that a subset of mature enteroendocrine cells (EECs), predominantly enterochromaffin cells, dedifferentiates to fully functional intestinal stem cells (ISCs) is novel, timely, and important. These cells dedifferentiate to ISCs not only in response to injury but also under basal homeostatic conditions. These novel findings provide a mechanism in which a specified cell can dedifferentiate and contribute to normal tissue plasticity as well as the development of EEC-derived intestinal tumors under pathologic conditions.

scholarly journals Non-canonical Wnt signaling promotes directed migration of intestinal stem cells to sites of injury

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daniel Jun-Kit Hu ◽  
Jina Yun ◽  
Justin Elstrott ◽  
Heinrich Jasper
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Migration ◽  
Wnt Signaling ◽  
Intestinal Epithelium ◽  
Enteroendocrine Cells ◽  
Intestinal Stem Cells ◽  
Canonical Wnt Signaling ◽  
Stem Cell Migration ◽  
Canonical Wnt

AbstractTissue regeneration after injury requires coordinated regulation of stem cell activation, division, and daughter cell differentiation, processes that are increasingly well understood in many regenerating tissues. How accurate stem cell positioning and localized integration of new cells into the damaged epithelium are achieved, however, remains unclear. Here, we show that enteroendocrine cells coordinate stem cell migration towards a wound in the Drosophila intestinal epithelium. In response to injury, enteroendocrine cells release the N-terminal domain of the PTK7 orthologue, Otk, which activates non-canonical Wnt signaling in intestinal stem cells, promoting actin-based protrusion formation and stem cell migration towards a wound. We find that this migratory behavior is closely linked to proliferation, and that it is required for efficient tissue repair during injury. Our findings highlight the role of non-canonical Wnt signaling in regeneration of the intestinal epithelium, and identify enteroendocrine cell-released ligands as critical coordinators of intestinal stem cell migration.

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 Phospho-regulation of Atoh1 is required for plasticity of secretory progenitors and tissue regeneration

2018 ◽  
Author(s):  
Goran Tomic ◽  
Edward Morrissey ◽  
Sarah Kozar ◽  
Shani Ben-Moshe ◽  
Alice Hoyle ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Intestinal Epithelium ◽  
Tissue Damage ◽  
Cell Activity ◽  
Lineage Tracing ◽  
Self Renewal ◽  
Regenerative Response ◽  
Stem Cell Activity ◽  
Chemical Colitis

SUMMARYThe intestinal epithelium is maintained by a small number of self-renewing stem cells in homeostasis. In addition committed progenitors can contribute to the functional stem cell compartment at a low level during homeostasis and substantially during regeneration following tissue damage. However the mechanism of, and requirement for, progenitor plasticity in mediating pathological response has not been demonstrated. Here we show that multisite phosphorylation of the transcription factor Atoh1 is required both for the contribution of secretory progenitors to the intestinal stem cell pool and for a robust regenerative response following damage. In lineage tracing experiments Atoh1+ cells (Atoh1(WT)CreERT2 mice) show stem cell activity by giving rise to multilineage intestinal clones both in the steady state and after tissue damage. Notably in the colonic epithelium a single generation of Atoh1+ progenitors sustains 1 in 15 stem cells. In an activating Atoh1(9S/T-A)CreERT2 line, the loss of phosphorylation sites on the Atoh1 protein promotes secretory differentiation and inhibits the contribution of these cells to self-renewal. Finally, in a chemical colitis model the Atoh1+ cells of Atoh1(9S/T-A)CreERT2 mice have reduced clonogenic capacity that impacts overall regenerative response of the epithelium. Thus progenitor plasticity plays an integral part in maintaining robust self-renewal in the intestinal epithelium and the balance between stem and progenitor fate behaviour is directly co-ordinated by Atoh1 multi-site phosphorylation.

scholarly journals aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation

2013 ◽  
Vol 202 (6) ◽  
pp. 887-900 ◽  
Author(s):  
Michaela T. Niessen ◽  
Jeanie Scott ◽  
Julia G. Zielinski ◽  
Susanne Vorhagen ◽  
Panagiota A. Sotiropoulou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Lineage Tracing ◽  
Premature Aging ◽  
Temporary Increase ◽  
Proliferative Potential ◽  
Cell Dynamics ◽  
Asymmetric Divisions

The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.

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 Asymmetric cell division-dominant neutral drift model for normal intestinal stem cell homeostasis

2019 ◽  
Vol 316 (1) ◽  
pp. G64-G74 ◽  
Author(s):  
Yoshitatsu Sei ◽  
Jianying Feng ◽  
Carson C. Chow ◽  
Stephen A. Wank
Keyword(s):  
Cell Division ◽  
Mitotic Spindle ◽  
Asymmetric Cell Division ◽  
Dominant Mode ◽  
Lineage Tracing ◽  
Intestinal Stem Cells ◽  
In Vivo Studies ◽  
Neutral Drift ◽  
Drift Model

The normal intestinal epithelium is continuously regenerated at a rapid rate from actively cycling Lgr5-expressing intestinal stem cells (ISCs) that reside at the crypt base. Recent mathematical modeling based on several lineage-tracing studies in mice shows that the symmetric cell division-dominant neutral drift model fits well with the observed in vivo growth of ISC clones and suggests that symmetric divisions are central to ISC homeostasis. However, other studies suggest a critical role for asymmetric cell division in the maintenance of ISC homeostasis in vivo. Here, we show that the stochastic branching and Moran process models with both a symmetric and asymmetric division mode not only simulate the stochastic growth of the ISC clone in silico but also closely fit the in vivo stem cell dynamics observed in lineage-tracing studies. In addition, the proposed model with highest probability for asymmetric division is more consistent with in vivo observations reported here and by others. Our in vivo studies of mitotic spindle orientations and lineage-traced progeny pairs indicate that asymmetric cell division is a dominant mode used by ISCs under normal homeostasis. Therefore, we propose the asymmetric cell division-dominant neutral drift model for normal ISC homeostasis. NEW & NOTEWORTHY The prevailing mathematical model suggests that intestinal stem cells (ISCs) divide symmetrically. The present study provides evidence that asymmetric cell division is the major contributor to ISC maintenance and thus proposes an asymmetric cell division-dominant neutral drift model. Consistent with this model, in vivo studies of mitotic spindle orientation and lineage-traced progeny pairs indicate that asymmetric cell division is the dominant mode used by ISCs under normal homeostasis.

scholarly journals Study on the Therapeutic Mechanism of LXGYD on Intestinal Stem Cells and Tight Junction Proteins in GI-ARS Rats

2021 ◽  
Author(s):  
Ziqiao Yan ◽  
Bofeng Yin ◽  
Yuguo Wang ◽  
Jian Feng ◽  
Qianyu Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Health Status ◽  
Tight Junction ◽  
Western Blotting ◽  
Rat Model ◽  
Protective Efficacy ◽  
Intestinal Stem Cells ◽  
Pathological Analysis ◽  
Chinese Herbal

Abstract Background: Gastrointestinal acute radiation injury syndrome (GI-ARS) is potentially lethal and may occur after exposure to high radiation doses. Various chemical and biological agents have been developed to treat GI-ARS. However, their clinical utility is limited as they induce serious adverse reactions at their effective doses. Chinese herbal medicines have attracted attention because of their protective efficacy and low toxicity in radiation exposure treatment. However, their cellular and molecular mechanisms remain unknown. Here, we investigated the effects of the Chinese herbal Liangxue-Guyuan-Yishen decoction (LXGYD) on the intestinal stem cells and signal pathways of a GI-ARS rat model. Currently, there are limited treatment methods available globally; LXGYD might be a potential therapeutic option for patients with GI-ARS. Methods: The rat GI-ARS model was prepared by whole-body irradiation with 10-Gy of 60Co-γ rays. Various LXGYD concentrations were intragastrically administered to the irradiated rats. Health status and survival of the rats were evaluated and the protective efficacy of LXGYD on the intestines was assayed by pathological analysis. The active principles in LXGYD were detected by liquid chromatography-mass spectrometry (LC-MS) and their potential targets and pathways were screened by network pharmacological analysis. Intestinal stem cell proliferation, intestinal epithelial tight junction (TJ) protein expression, and regulatory pathways were explored by immunohistochemistry (IHC), western blotting (WB), and real-time quantitative polymerase chain reaction (RT-qPCR), respectively.Results: LXGYD administration significantly improved health status and survival in GI-ARS rats. The pathological analysis showed that LXGYD ameliorated radiation-induced intestinal injury. The LXGYD infusion significantly promoted LGR5+ stem cell regeneration in the ileal crypts, upregulated TJ proteins, and accelerated crypt reconstruction in the irradiated rats in a dose-dependent manner. LC-MS revealed ≥ 13 LXGYD constituents that might contribute to its protective effects. Involvement of the WNT and MEK/ERK pathways in intestinal repair and recovery were screened by network pharmacology analysis and validated by western blotting.Conclusions: The present study disclosed a heretofore unrecognized role of the Chinese herbal LXGYD in rescuing the intestinal stem cells of a GI-ARS rat model. It also showed that the WNT and MEK/ERK pathways may be involved in LXGYD-mediated intestinal regeneration in GI-ARS.

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.

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