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.

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 Interplay among p21Waf1/Cip1, MUSASHI-1 and Krüppel-like factor 4 in activation of Bmi1-CreER reserve intestinal stem cells after gamma radiation-induced injury

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emilia J. Orzechowska ◽  
Takahito Katano ◽  
Agnieszka B. Bialkowska ◽  
Vincent W. Yang
Keyword(s):  
Stem Cells ◽  
Gamma Radiation ◽  
Therapeutic Potential ◽  
Mrna Translation ◽  
Negative Regulator ◽  
Intestinal Stem Cells ◽  
Quiescent State ◽  
Γ Radiation ◽  
Regenerative Response ◽  
Radiation Induced

Abstract Gamma radiation is a commonly used adjuvant treatment for abdominally localized cancer. Since its therapeutic potential is limited due to gastrointestinal (GI) syndrome, elucidation of the regenerative response following radiation-induced gut injury is needed to develop a preventive treatment. Previously, we showed that Krüppel-like factor 4 (KLF4) activates certain quiescent intestinal stem cells (ISCs) marked by Bmi1-CreER to give rise to regenerating crypts following γ irradiation. In the current study, we showed that γ radiation-induced expression of p21Waf1/Cip1 in Bmi1-CreER cells is likely mitigated by MUSASHI-1 (MSI1) acting as a negative regulator of p21Waf1/Cip1 mRNA translation, which promotes exit of the Bmi1-CreER cells from a quiescent state. Additionally, Bmi1-specific Klf4 deletion resulted in decreased numbers of MSI1+ cells in regenerating crypts compared to those of control mice. We showed that KLF4 binds to the Msi1 promoter and activates its expression in vitro. Since MSI1 has been shown to be crucial for crypt regeneration, this finding elucidates a pro-proliferative role of KLF4 during the postirradiation regenerative response. Taken together, our data suggest that the interplay among p21Waf1/Cip1, MSI1 and KLF4 regulates Bmi1-CreER cell survival, exit from quiescence and regenerative potential upon γ radiation-induced injury.

Directed Differentiation into Neural Lineages and Therapeutic Potential of Porcine Embryonic Stem Cells in Rat Parkinson's Disease Model

2010 ◽  
Vol 12 (4) ◽  
pp. 447-461 ◽  
Author(s):  
Jenn-Rong Yang ◽  
Chia-Hsin Liao ◽  
Cheng-Yoong Pang ◽  
Lynn Ling-Huei Huang ◽  
Yu-Ting Lin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Embryonic Stem Cells ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Embryonic Stem ◽  
Directed Differentiation

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

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 A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1037 ◽  
Author(s):  
Lucia Mercedes Ruiz-Perera ◽  
Johannes Friedrich Wilhelm Greiner ◽  
Christian Kaltschmidt ◽  
Barbara Kaltschmidt
Keyword(s):  
Stem Cells ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Transcript Level ◽  
Human Stem Cells ◽  
Human Neural Stem Cells ◽  
Essential Function

The molecular mechanisms underlying fate decisions of human neural stem cells (hNSCs) between neurogenesis and gliogenesis are critical during neuronal development and neurodegenerative diseases. Despite its crucial role in the murine nervous system, the potential role of the transcription factor NF-κB in the neuronal development of hNSCs is poorly understood. Here, we analyzed NF-κB subunit distribution during glutamatergic differentiation of hNSCs originating from neural crest-derived stem cells. We observed several peaks of specific NF-κB subunits. The most prominent nuclear peak was shown by c-REL subunit during a period of 2–5 days after differentiation onset. Furthermore, c-REL inhibition with pentoxifylline (PTXF) resulted in a complete shift towards oligodendroglial fate, as demonstrated by the presence of OLIG2+/O4+-oligodendrocytes, which showed PDGFRα, NG2 and MBP at the transcript level. In addition c-REL impairment further produced a significant decrease in neuronal survival. Transplantation of PTXF-treated predifferentiated hNSCs into an ex vivo oxidative-stress-mediated demyelination model of mouse organotypic cerebellar slices further led to integration in the white matter and differentiation into MBP+ oligodendrocytes, validating their functionality and therapeutic potential. In summary, we present a human cellular model of neuronal differentiation exhibiting a novel essential function of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis which will potentially be relevant for multiple sclerosis and schizophrenia.

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