Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals

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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GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Cells ◽

10.3390/cells10020225 ◽

2021 ◽

Vol 10 (2) ◽

pp. 225

Author(s):

Claire Racaud-Sultan ◽

Nathalie Vergnolle

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adult Stem Cells ◽

Glycogen Synthase ◽

Inflammatory Diseases ◽

Adult Stem Cell ◽

Leukemic Cells ◽

Cell Phenotype ◽

Epithelial Regeneration ◽

Cell Functions

In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

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

Biomedicines ◽

10.3390/biomedicines8120560 ◽

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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Designing and Engineering Stem Cell Niches

MRS Bulletin ◽

10.1557/mrs2010.527 ◽

2010 ◽

Vol 35 (8) ◽

pp. 591-596 ◽

Cited By ~ 5

Author(s):

Ana I. Teixeira ◽

Ola Hermanson ◽

Carsten Werner

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Biology ◽

Chemical Engineering ◽

Polyglycolic Acid ◽

Differentiated Cells ◽

Extracellular Matrix Components ◽

Stem Cell Niches

AbstractStem cells have received a lot of attention due to great promises in medical treatment, for example, by replacing lost and sick cells and re-constituting cell populations. There are several classes of stem cells, including embryonic, fetal, and adult tissue specific. More recently, the generation of so-called induced pluripotent stem (iPS) cells from differentiated cells has been established. Common criteria for all types of stem cells include their ability to self-renew and to retain their ability to differentiate in response to specific cues. These characteristics, as well as the instructive steering of the cells into differentiation, are largely dependent on the microenvironment surrounding the cells. Such “stem cell friendly” microenvironments, provided by structural and biochemical components, are often referred to as niches. Biomaterials offer attractive solutions to engineer functional stem cell niches and to steer stem cell state and fatein vitroas well asin vivo. Among materials used so far, promising results have been achieved with low-toxicity and biodegradable polymers, such as polyglycolic acid and related materials, as well as other polymers used as structural “scaffolds” for engineering of extracellular matrix components. To improve the efficiency of stem cell control and the design of the biomaterials, interfaces among stem cell research, developmental biology, regenerative medicine, chemical engineering, and materials research are rapidly developing. Here we provide an introduction to stem cell biology and principles of niche engineering and give an overview of recent advancements in stem cell niche engineering from two stem cell systems—blood and brain.

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Resolving stem and progenitor cells in the adult mouse incisor through gene co-expression analysis

eLife ◽

10.7554/elife.24712 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 19

Author(s):

Kerstin Seidel ◽

Pauline Marangoni ◽

Cynthia Tang ◽

Bahar Houshmand ◽

Wen Du ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Expression Analysis ◽

Adult Mouse ◽

Deep Understanding ◽

Lineage Tracing ◽

Differentiated Cells ◽

Mouse Incisor ◽

Stem Cell Niches

Investigations into stem cell-fueled renewal of an organ benefit from an inventory of cell type-specific markers and a deep understanding of the cellular diversity within stem cell niches. Using the adult mouse incisor as a model for a continuously renewing organ, we performed an unbiased analysis of gene co-expression relationships to identify modules of co-expressed genes that represent differentiated cells, transit-amplifying cells, and residents of stem cell niches. Through in vivo lineage tracing, we demonstrated the power of this approach by showing that co-expression module members Lrig1 and Igfbp5 define populations of incisor epithelial and mesenchymal stem cells. We further discovered that two adjacent mesenchymal tissues, the periodontium and dental pulp, are maintained by distinct pools of stem cells. These findings reveal novel mechanisms of incisor renewal and illustrate how gene co-expression analysis of intact biological systems can provide insights into the transcriptional basis of cellular identity.

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

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00036.2018 ◽

2018 ◽

Vol 315 (4) ◽

pp. G495-G510 ◽

Cited By ~ 14

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.

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R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon

Nature Communications ◽

10.1038/s41467-019-12349-5 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 15

Author(s):

Christine Harnack ◽

Hilmar Berger ◽

Agne Antanaviciute ◽

Ramon Vidal ◽

Sascha Sauer ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Wnt Signaling ◽

Cell Injury ◽

Cell Recovery ◽

Epithelial Repair ◽

Epithelial Regeneration ◽

Differentiated Cells ◽

Two Populations ◽

Crypt Base

Abstract The colonic epithelial turnover is driven by crypt-base stem cells that express the R-spondin receptor Lgr5. Signals that regulate epithelial regeneration upon stem cell injury are largely unknown. Here, we explore the dynamics of Wnt signaling in the colon. We identify two populations of cells with active Wnt signaling: highly proliferative Lgr5+/Axin2+ cells, as well as secretory Lgr5−/Axin2+ cells. Upon Lgr5+ cell depletion, these cells are recruited to contribute to crypt regeneration. Chemical injury induced by DSS leads to a loss of both Lgr5+ cells and Axin2+ cells and epithelial regeneration is driven by Axin2− cells, including differentiated Krt20+ surface enterocytes. Regeneration requires stromal Rspo3, which is present at increased levels upon injury and reprograms Lgr5− but Lgr4+ differentiated cells. In contrast, depletion of stromal Rspo3 impairs crypt regeneration, even upon mild injury. We demonstrate that Rspo3 is essential for epithelial repair via induction of Wnt signaling in differentiated cells.

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

Nature Communications ◽

10.1038/s41467-021-27384-4 ◽

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.

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Stem Cell Niches in Glioblastoma: A Neuropathological View

BioMed Research International ◽

10.1155/2014/725921 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 24

Author(s):

Davide Schiffer ◽

Marta Mellai ◽

Laura Annovazzi ◽

Valentina Caldera ◽

Angela Piazzi ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Stem Cell ◽

Tumor Cells ◽

Therapeutic Target ◽

Molecular Mechanisms ◽

Mechanisms Of Resistance ◽

Differentiated Cells ◽

Thin Ring ◽

Stem Cell Niches

Glioblastoma (GBM) stem cells (GSCs), responsible for tumor growth, recurrence, and resistance to therapies, are considered the real therapeutic target, if they had no molecular mechanisms of resistance, in comparison with the mass of more differentiated cells which are insensitive to therapies just because of being differentiated and nonproliferating. GSCs occur in tumor niches where both stemness status and angiogenesis are conditioned by the microenvironment. In both perivascular and perinecrotic niches, hypoxia plays a fundamental role. Fifteen glioblastomas have been studied by immunohistochemistry and immunofluorescence for stemness and differentiation antigens. It has been found that circumscribed necroses develop inside hyperproliferating areas that are characterized by high expression of stemness antigens. Necrosis developed inside them because of the imbalance between the proliferation of tumor cells and endothelial cells; it reduces the number of GSCs to a thin ring around the former hyperproliferating area. The perinecrotic GSCs are nothing else that the survivors remnants of those populating hyperproliferating areas. In the tumor, GSCs coincide with malignant areas so that the need to detect where they are located is not so urgent.

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Epithelial Regeneration after Doxorubicin Arises Primarily from Early Progeny of Active Intestinal Stem Cells

SSRN Electronic Journal ◽

10.2139/ssrn.3593526 ◽

2020 ◽

Author(s):

Breanna Sheahan ◽

Ally N. Freeman ◽

Theresa M. Keeley ◽

Linda C. Samuelson ◽

Jatin Roper ◽

...

Keyword(s):

Stem Cells ◽

Intestinal Stem Cells ◽

Epithelial Regeneration

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Metabolic Regulation and Related Molecular Mechanisms in Various Stem Cell Functions

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200512105347 ◽

2020 ◽

Vol 15 (6) ◽

pp. 531-546 ◽

Cited By ~ 1

Author(s):

Hwa-Yong Lee ◽

In-Sun Hong

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Oxidative Phosphorylation ◽

Metabolic Pathways ◽

Critical Role ◽

The Self ◽

Specific Cell ◽

Differentiation Potential ◽

Self Renewal ◽

Cell Functions

Recent studies on the mechanisms that link metabolic changes with stem cell fate have deepened our understanding of how specific metabolic pathways can regulate various stem cell functions during the development of an organism. Although it was originally thought to be merely a consequence of the specific cell state, metabolism is currently known to play a critical role in regulating the self-renewal capacity, differentiation potential, and quiescence of stem cells. Many studies in recent years have revealed that metabolic pathways regulate various stem cell behaviors (e.g., selfrenewal, migration, and differentiation) by modulating energy production through glycolysis or oxidative phosphorylation and by regulating the generation of metabolites, which can modulate multiple signaling pathways. Therefore, a more comprehensive understanding of stem cell metabolism could allow us to establish optimal culture conditions and differentiation methods that would increase stem cell expansion and function for cell-based therapies. However, little is known about how metabolic pathways regulate various stem cell functions. In this context, we review the current advances in metabolic research that have revealed functional roles for mitochondrial oxidative phosphorylation, anaerobic glycolysis, and oxidative stress during the self-renewal, differentiation and aging of various adult stem cell types. These approaches could provide novel strategies for the development of metabolic or pharmacological therapies to promote the regenerative potential of stem cells and subsequently promote their therapeutic utility.

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