The regulatory niche of intestinal stem cells

Sailaja, Badi Sri; He, Xi; Li, Linheng

doi:10.1113/jp271931

Cited by 93 publications

(68 citation statements)

References 74 publications

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“…Stem cell function and regulation of stem cell proliferation are mediated by the stem cell niche (15). In the gut, in addition to Paneth cells, stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are postulated to be important components of the niche, but their precise role and the requirement for mesenchymal cells for normal stem cell function are still being elucidated (1,9,11,22).…”

Section: Introductionmentioning

confidence: 99%

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Vishy

Swietlicki

Gazit

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Stem cell therapy is a potential therapeutic approach for disorders characterized by intestinal injury or loss of functional surface area. Stem cell function and proliferation are mediated by the stem cell niche. Stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are important but poorly studied components of the stem cell niche. To examine the role of ISEMFs, we have previously generated mice with deletion of epimorphin ( Epim), an ISEMF protein and member of the syntaxin family of intracellular vesicle docking proteins that regulate cell secretion. Herein we explore the mechanisms for previous observations that Epim deletion increases gut crypt cell proliferation, crypt fission, and small bowel length in vivo. Stem cell-derived crypt culture techniques were used to explore the interaction between enteroids and myofibroblasts from Epim and WT mice. Enteroids cocultured with ISEMFS had increased growth and crypt-like budding compared with enteroids cultured without stromal support. Epim deletion in ISEMFs resulted in increased enteroid budding and surface area compared with cocultures with wild-type (WT) ISEMFs. In primary crypt cultures, Epim enteroids had significantly increased surface area and budding compared with WTs. However, stem cell assays comparing the number of Epim vs. WT colony-forming units after first passage showed no differences in the absence of ISEMF support. Epim vs. WT ISEMFs had increased Wnt4 expression, and addition of Wnt4 to WT cocultures enhanced budding. We conclude that ISEMFs play an important role in the stem cell niche. Epim regulates stem cell proliferation and differentiation via stromal contributions to the niche microenvironment. NEW & NOTEWORTHY The role of subepithelial intestinal myofibroblasts (ISEMFs) in the gut stem cell niche is controversial. We provide novel evidence supporting ISEMFs as important niche contributors. We show that the in vivo intestinal effects of deletion of myofibroblast Epim can be recapitulated in crypt stem cell cultures in vitro. ISEMFs support cocultured stem cell proliferation and enteroid growth, and these effects are augmented by deletion of Epim, a syntaxin that regulates myofibroblast cell secretion.

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Section: Introductionmentioning

confidence: 99%

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Vishy

Swietlicki

Gazit

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…This developmental coronary blood vessel differentiation patterning seems to be dependent on the Notch signaling pathway, given that Notch1, 3 and 4 and the Notch ligand DII4 are specifically expressed in arterial endothelial cells and control EphrinB2 expression (Lawson et al, ). Thus, coronary expression of Notch pathway receptors and ligands, which are also present in other stem cell niches (Sailaja et al, ; Seshadri and Qu, ; Kyrousi et al, ), suggests that blood vessels could be a pivotal element of potential CI niches.…”

Section: The Basic Structure Of the Adult CImentioning

confidence: 99%

Development of the Myocardial Interstitium

Pogontke

Guadix

Ruiz‐Villalba

et al. 2018

The Anatomical Record

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The space between cardiac myocytes is commonly referred‐to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple cell types, extracellular matrix molecules, and instructive signals interact to crucially support heart homeostasis and promote cardiac responses to normal and pathologic stimuli. Despite the biomedical and clinical relevance of the CI, its detailed cellular structure remains to be elucidated. In this review, we will dissect the organization of the cardiac interstitium by following its changing cellular and molecular composition from embryonic developmental stages to adulthood, providing a systematic analysis of the biological components of the CI. The main goal of this review is to contribute to our understanding of the CI roles in health and disease. Anat Rec, 302:58–68, 2019. © 2018 Wiley Periodicals, Inc.

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“…TACs differentiate into a variety of cell lineages including enterocytes, enteroendocrine cells, Goblet cells, and Paneth cells. While Paneth cells remain at the crypt bottom and interdigitate with ISCs, the remaining cell types migrate upward along the crypt-villus axis as they differentiate into their various specialized roles (Sailaja et al, 2016). Under homeostatic conditions, actively cycling ISCs are responsible for the repopulation of the entire intestinal epithelium; In the event of injury however, slowcycling reserve ISCs (rISCs) mediate tissue repair with assistance from a subset of differentiated cells which reacquire their 'stem' state through mechanisms of cellular plasticity (Li and Clevers, 2010, Scoville et al, 2008, Yousefi et al, 2017.…”

Section: Introductionmentioning

confidence: 99%

“…The collection of structural, molecular, and cellular components within the stem cell's immediate vicinity are collectively known as the niche, and changes in any of these components will alter a stem cell's behavior to better meet the body's needs. ISC selfrenewal, cell cycle state, metabolic activity, lineage specification, and many other important processes in stem cells are all controlled through niche dynamics (Sailaja et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A Holistic Analysis of the Intestinal Stem Cell Niche Network

Pim

et al. 2019

Preprint

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Although many studies into the intestinal stem cell (ISC) niche have been carried out, they have focused on the role of a single cell type or molecular signal. However, no holistic comparisons of the predominant cell types and signals present within the intestinal mucosa have been conducted to date. We utilize bulk RNA sequencing to profile 20 different mucosal cell types covering four major cell categories: epithelial, stromal, endothelial and immune. We further examined the stromal signaling environment using scRNAseq to provide a more comprehensive view of the signaling microenvironment within the intestinal mucosa. We identified the primary signals for the major ISC regulatory pathways and their respective cellular sources. Our analysis suggests that a 'niche network' exists, with no single cell type being responsible for ISC self-renewal, proliferation, or differentiation; rather, each cell type within the network carries out specific functions in a highly cooperative and coordinated manner. KeywordsStem Cell Niche, Intestinal Stem Cells, ISC, RNA-Sequencing As expected, principle component analysis of the various transcriptomes resulted in the cell types clustering according to their categorical distinctions ( Fig. 1G). To briefly summarize, Grem1 CreErt2 + cells adopted a unique position between stromal and epithelial cells. Nestin GFP + and Ncad tdT + cells clustered together, consistent with their overlap and distribution pattern. Intriguingly, Ng2 dsR + and Dmp1 Cre + cells were transcriptomically similar, yet showed differences in several genes important to cellular function ( Fig. S1B). Innate lymphoid type 3 cells (ILC3) were positioned between adaptive T Cells and Innate Immune Dendritic cells and Macrophages (Fig. 1G). Characterization of Genetic Models and Stromal PopulationsBoth Nestin GFP + and Ncad CreErt2 + stromal cells were present from the smooth muscle to the villus tips ( Fig. 2A-B) and possessed somewhat similar distributions and morphologies to the niche cells described within the bone marrow. Though there was considerable overlap and similarities between these genetic markers, several differences were apparent. Ncad CreErt2 + cells were more likely to encircle the vasculature with a flattened morphology, while Nestin GFP + cells frequently laid on top of these cells and possessed long filopodia which connect with one another ( Fig. S2A-E) Ncad CreErt2 + cells were more likely to be present at the lower "ring", while Nestin GFP + were more likely to localize to the isthmus. Ng2 dsR + cells also overlapped with Nestin GFP + cells but were the only cell type examined that exhibited a strong spatial bias within the mucosa, being almost exclusively found within the villi (Fig. 2C,S2B).Unfortunately, their morphological characteristics could not be determined due to the tendency of the dsRed protein to form aggregates, preventing even cytosolic distribution.Dmp1 Cre + cells showed the greatest amount of morphological and positional diversity, likely due to their constitutively active Cre, wh...

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The regulatory niche of intestinal stem cells

Cited by 93 publications

References 74 publications

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment

Development of the Myocardial Interstitium

A Holistic Analysis of the Intestinal Stem Cell Niche Network

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