scholarly journals Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo

EMBO Reports ◽  
2011 ◽  
Vol 12 (6) ◽  
pp. 558-564 ◽  
Author(s):  
Roxana C Mustata ◽  
Tom Van Loy ◽  
Anne Lefort ◽  
Frédérick Libert ◽  
Sandra Strollo ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Differentiation ◽  
Ex Vivo ◽  
Paneth Cell ◽  
Intestinal Stem Cells

scholarly journals Robust differentiation of human enteroendocrine cells from intestinal stem cells

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Daniel Zeve ◽  
Eric Stas ◽  
Joshua de Sousa Casal ◽  
Prabhath Mannam ◽  
Wanshu Qi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Differentiation ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Intestinal Stem Cells ◽  
Directed Differentiation ◽  
Hormone Production ◽  
Receptor Signaling Pathway ◽  
Endocannabinoid Receptor

AbstractEnteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of the endocannabinoid receptor signaling pathway, JNK, and FOXO1, known to mediate endodermal development and/or hormone production, together with directed differentiation of human ISCs from the duodenum and rectum. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, GIP, CCK, GLP-1 and PYY upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.

scholarly journals Robust differentiation of human enteroendocrine cells from intestinal stem cells

2020 ◽  
Author(s):  
Daniel Zeve ◽  
Eric Stas ◽  
Xiaolei Yin ◽  
Sarah Dubois ◽  
Manasvi S. Shah ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Differentiation ◽  
Small Molecules ◽  
Energy Homeostasis ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Transcriptional Regulators ◽  
Intestinal Stem Cells ◽  
Directed Differentiation ◽  
Hormone Production

ABSTRACTEnteroendocrine (EE) cells are the most abundant hormone-producing cells in humans and are critical regulators of energy homeostasis and gastrointestinal function. Challenges in converting human intestinal stem cells (ISCs) into functional EE cells, ex vivo, have limited progress in elucidating their role in disease pathogenesis and in harnessing their therapeutic potential. To address this, we employed small molecule targeting of key transcriptional regulators, GATA4, JNK and FOXO1, known to mediate endodermal development and hormone production, together with directed differentiation of human ISCs. We observed marked induction of EE cell differentiation and gut-derived expression and secretion of SST, 5HT, and GIP upon treatment with various combinations of three small molecules: rimonabant, SP600125 and AS1842856. Robust differentiation strategies capable of driving human EE cell differentiation is a critical step towards understanding these essential cells and the development of cell-based therapeutics.

Ex Vivo Culture of Primary Intestinal Stem Cells in Collagen Gels and Foams

2014 ◽  
Vol 1 (1) ◽  
pp. 37-42 ◽  
Author(s):  
Haisheng Peng ◽  
Nitya Poovaiah ◽  
Michael Forrester ◽  
Eric Cochran ◽  
Qun Wang
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Intestinal Stem Cells ◽  
Collagen Gels ◽  
Ex Vivo Culture

The Enteric Microbiota Regulates Paneth Cell Number and Function Without Affecting Intestinal Stem Cells

2017 ◽  
Vol 152 (5) ◽  
pp. S13 ◽  
Author(s):  
Alexi A. Schoenborn ◽  
Richard von Furstenberg ◽  
Smrithi Valsaraj ◽  
Farah S. Hussain ◽  
Molly Stein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Paneth Cell ◽  
Cell Number ◽  
Intestinal Stem Cells ◽  
And Function

scholarly journals Source and Impact of the EGF Family of Ligands on Intestinal Stem Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Helen E. Abud ◽  
Wing Hei Chan ◽  
Thierry Jardé
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Ex Vivo ◽  
Intestinal Stem Cells ◽  
Intestinal Epithelial ◽  
Neuregulin 1 ◽  
Epithelial Development ◽  
Epidermal Growth ◽  
Egf Family

Epidermal Growth Factor (EGF) has long been known for its role in promoting proliferation of intestinal epithelial cells. EGF is produced by epithelial niche cells at the base of crypts in vivo and is routinely added to the culture medium to support the growth of intestinal organoids ex vivo. The recent identification of diverse stromal cell populations that reside underneath intestinal crypts has enabled the characterization of key growth factor cues supplied by these cells. The nature of these signals and how they are delivered to drive intestinal epithelial development, daily homeostasis and tissue regeneration following injury are being investigated. It is clear that aside from EGF, other ligands of the family, including Neuregulin 1 (NRG1), have distinct roles in supporting the function of intestinal stem cells through the ErbB pathway.

scholarly journals The murine intestinal stem cells are highly sensitive to the modulation of the T3/TRα1-dependent pathway

Development ◽  
2021 ◽  
pp. dev.194357
Author(s):  
Matthias Godart ◽  
Carla Frau ◽  
Diana Farhat ◽  
Maria Virginia Giolito ◽  
Catherine Jamard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Ex Vivo ◽  
Cell Activity ◽  
Crypt Cell ◽  
Intestinal Stem Cells ◽  
Gut Development ◽  
Crypt Cell Proliferation ◽  
Depth Analysis

The thyroid hormone T3 and its nuclear receptor TRα1 control gut development and homeostasis through the modulation of intestinal crypt cell proliferation. Despite increasing data, in depth analysis on their specific action on intestinal stem cells is lacking.By using ex vivo 3D organoid cultures and molecular approaches we observed early responses to T3 involving the T3-metabolizing enzyme Dio1 and the transporter Mct10, accompanied by a complex response of stem cell- and progenitor-enriched genes. Interestingly, specific TRα1 loss-of-function (inducible or constitutive) was responsible for low ex vivo organoid development and impaired stem cell activity. T3-treatment of animals in vivo not only confirmed the positive action of this hormone on crypt cell proliferation but also demonstrated its key action in modulating i) the number of the stem cells, ii) the expression of their specific markers and iii) the commitment of progenitors into lineage-specific differentiation.In conclusion, T3 treatment or TRα1 modulation has a rapid and strong effect on intestinal stem cells, broadening our perspectives in the study of T3/TRα1-dependent signaling in these cells.

scholarly journals High-throughput organoid screening enables engineering of intestinal epithelial composition

2020 ◽  
Author(s):  
Benjamin E. Mead ◽  
Kazuki Hattori ◽  
Lauren Levy ◽  
Marko Vukovic ◽  
Daphne Sze ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
High Throughput ◽  
Intestinal Epithelium ◽  
Paneth Cell ◽  
Stem Cell Differentiation ◽  
Biological Targets ◽  
Small Intestinal

SummaryBarrier tissue epithelia play an essential role in maintaining organismal homeostasis, and changes in their cellular composition have been observed in multiple human diseases. Within the small intestinal epithelium, adult stem cells integrate diverse signals to regulate regeneration and differentiation, thereby establishing overall cellularity. Accordingly, directing stem cell differentiation could provide a tractable approach to alter the abundance or quality of specialized cells of the small intestinal epithelium, including the secretory Paneth, goblet, and enteroendocrine populations. Yet, to date, there has been a lack of suitable tools and rigorous approaches to identify biological targets and pharmacological agents that can modify epithelial composition to enable causal testing of disease-associated changes with novel therapeutic candidates. To empower the search for epithelia-modifying agents, we establish a first-of-its-kind high-throughput phenotypic organoid screen. We demonstrate the ability to screen thousands of samples and uncover biological targets and associated small molecule inhibitors which translate to in vivo. This approach is enabled by employing a functional, cell-type specific, scalable assay on an organoid model designed to represent the physiological cues of in vivo Paneth cell differentiation from adult intestinal stem cells. Further, we miniaturize and adapt the organoid culture system to enable automated plating and screening, thereby providing the ability to test thousands of samples. Strikingly, in our screen we identify inhibitors of the nuclear exporter Xpo1 modulate stem cell fate commitment by inducing a pan-epithelial stress response combined with an interruption of mitogen signaling in cycling intestinal progenitors, thereby significantly increasing the abundance of Paneth cells independent of known WNT and Notch differentiation cues. We extend our observation in vivo, demonstrating that oral administration of Xpo1 inhibitor KPT-330 at doses 1,000-fold lower than conventionally used in hematologic malignancies increases Paneth cell abundance. In total, we provide a framework to identify novel biological cues and therapeutic leads to rebalance intestinal stem cell differentiation and modulate epithelial tissue composition via high-throughput phenotypic screening in rationally-designed organoid model of differentiation.

scholarly journals The enteric microbiota regulates jejunal Paneth cell number and function without impacting intestinal stem cells

Gut Microbes ◽  
2018 ◽  
Vol 10 (1) ◽  
pp. 45-58 ◽  
Author(s):  
Alexi A. Schoenborn ◽  
Richard J. von Furstenberg ◽  
Smrithi Valsaraj ◽  
Farah S. Hussain ◽  
Molly Stein ◽  
...  
Keyword(s):  
Stem Cells ◽  
Paneth Cell ◽  
Cell Number ◽  
Intestinal Stem Cells ◽  
And Function

scholarly journals PDGFRα+ pericryptal stromal cells are the critical source of Wnts and RSPO3 for murine intestinal stem cells in vivo

2018 ◽  
Vol 115 (14) ◽  
pp. E3173-E3181 ◽  
Author(s):  
Gediminas Greicius ◽  
Zahra Kabiri ◽  
Kristmundur Sigmundsson ◽  
Chao Liang ◽  
Ralph Bunte ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Niche ◽  
Ex Vivo ◽  
Paneth Cell ◽  
Intestinal Stem Cells ◽  
Intestinal Stem Cell ◽  
Intestinal Crypt ◽  
Proliferation And Differentiation ◽  
Cell Niche

Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5-expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis. RSPO3 is highly expressed in pericryptal myofibroblasts in the lamina propria and is several orders of magnitude more potent than RSPO1 in stimulating both Wnt/β-catenin signaling and organoid growth. Stromal Rspo3 ablation ex vivo resulted in markedly decreased organoid growth that was rescued by exogenous RSPO3 protein. Pdgf receptor alpha (PdgfRα) is known to be expressed in pericryptal myofibroblasts. We therefore evaluated if PdgfRα identified the key stromal niche cells. In vivo, Porcn excision in PdgfRα+ cells blocked intestinal crypt formation, demonstrating that Wnt production in the stroma is both necessary and sufficient to support the intestinal stem-cell niche. Mice with Rspo3 excision in the PdgfRα+ cells had decreased intestinal crypt Wnt/β-catenin signaling and Paneth cell differentiation and were hypersensitive when stressed with dextran sodium sulfate. The data support a model of the intestinal stem-cell niche regulated by both Wnts and RSPO3 supplied predominantly by stromal pericryptal myofibroblasts marked by PdgfRα.

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