scholarly journals Dietary lipids modulate Notch signaling and influence adult intestinal development and metabolism in Drosophila

2018 ◽  
Author(s):  
Rebecca Obniski ◽  
Matthew Sieber ◽  
Allan C. Spradling
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Notch Signaling ◽  
Cell Function ◽  
Dietary Cholesterol ◽  
Adult Life ◽  
Notch Pathway ◽  
Stem Cell Differentiation ◽  
Nuclear Hormone Receptor ◽  
Dietary Lipids

SummaryTissue homeostasis is a complex balance of developmental signals and environmental cues that dictate stem cell function. However, it remains poorly understood how nutrients interface with developmental pathways. Using the Drosophila midgut as a model we found that during the first four days of adult life, dietary lipids including cholesterol, determine how many enteroendocrine (ee) cells differentiate and persist in the posterior midgut where lipids are preferentially absorbed. The nuclear hormone receptor Hr96 which functions to control sterol trafficking, storage, and utilization, is required for sterol-mediated changes in ee number. Dietary cholesterol influences new intestinal epithelial cell differentiation from stem cells by altering the level and persistance of Notch signaling. Exogenous lipids modulate signaling by changing the stability of the Delta ligand and Notch intracellular domain and their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues such as the ovary, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in ee number in young animals contribute to a metabolic program adapted to the prevailing nutrient environment that persists after the diet changes. A low sterol diet also slows the proliferation of enteroendocrine tumors initiated by disruptions in the Notch pathway. These studies show that a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.

scholarly journals Clonal inactivation of telomerase promotes accelerated stem cell differentiation

2021 ◽  
Author(s):  
Kazuteru Hasegawa ◽  
Yang Zhao ◽  
Alina Garbuzov ◽  
M. Ryan Corces ◽  
Lu Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Cell Function ◽  
Stem Cell Differentiation ◽  
Lineage Tracing ◽  
Open Chromatin ◽  
Loss Of Function ◽  
Direct Role ◽  
A Genome

SummaryTelomerase is intimately associated with stem cells and upregulated in cancer, where it serves essential roles through its catalytic action in elongating telomeres, nucleoprotein caps that protect chromosome ends1. Overexpression of the telomerase reverse transcriptase (TERT) enhances cell proliferation through telomere-independent means, yet definitive evidence for such a direct role in stem cell function has yet to be revealed through loss-of-function studies. Here, we show that conditional deletion of TERT in spermatogonial stem cells (SSCs) markedly impairs competitive clone formation. Using lineage-tracing from the Tert locus, we find that TERT-expressing SSCs yield long-lived clones, but that selective TERT-inactivation in SSCs causes accelerated stem cell differentiation thereby disrupting clone formation. This requirement for TERT in clone formation is bypassed by expression of a catalytically inactive TERT transgene and occurs independently of the canonical telomerase complex. TERT inactivation induces a genome-wide reduction in open chromatin evident in purified SSCs, but not in committed progenitor cells. Loss of TERT causes reduced activity of the MYC oncogene and transgenic expression of MYC in TERT-deleted SSCs efficiently rescues clone formation. These data reveal a required catalytic activity-independent role for TERT in preventing stem cell differentiation, forge a genetic link between TERT and MYC and suggest new means by which TERT may promote tumorigenesis.

scholarly journals Activated Notch signaling cascade is correlated with stem cell differentiation toward absorptive progenitors after massive small bowel resection in a rat

2017 ◽  
Vol 313 (3) ◽  
pp. G247-G255 ◽  
Author(s):  
Igor Sukhotnik ◽  
Arnold G. Coran ◽  
Yulia Pollak ◽  
Eviatar Kuhnreich ◽  
Drora Berkowitz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Small Bowel ◽  
Notch Signaling ◽  
Bowel Resection ◽  
Stem Cell Differentiation ◽  
Small Bowel Resection ◽  
Notch Signaling Pathway ◽  
Massive Small Bowel Resection

Notch signaling is thought to act to drive cell versification in the lining of the small intestine. The purpose of the present study was to evaluate the role of the Notch signaling pathway in stem cell differentiation in the late stages of intestinal adaptation after massive small bowel resection in a rat. Male Sprague-Dawley rats were randomly assigned to one of two experimental groups of eight rats each: Sham rats underwent bowel transection and reanastomosis, while SBS rats underwent 75% small bowel resection. Rats were euthanized on day 14. Illumina's Digital Gene Expression (DGE) analysis was used to determine Notch signaling gene expression profiling. Notch-related gene and protein expression was determined using real-time PCR, Western blot analysis, and immunohistochemistry. From seven investigated Notch-related (by DGE analysis) genes, six genes were upregulated in SBS vs. control animals with a relative change in gene expression level of 20% or more. A significant upregulation of Notch signaling-related genes in resected animals was accompanied by a significant increase in Notch-1 protein levels (Western blot analysis) and a significant increase in the number of Notch1 and Hes1 (target gene)-positive cells (immunohistochemistry) compared with sham animals. Evaluation of cell differentiation has shown a strong increase in total number of absorptive cells (unchanged secretory cells) compared with control rats. In conclusion, 2 wk after bowel resection in rats, stimulated Notch signaling directs the crypt cell population toward absorptive progenitors. NEW & NOTEWORTHY This study provides novel insight into the mechanisms of cell proliferation following massive small bowel resection. We show that 2 wk after bowel resection in rats, enhanced stem cell activity was associated with stimulated Notch signaling pathway. We demonstrate that activated Notch signaling cascade directs the crypt cell population toward absorptive progenitors.

scholarly journals Mitochondria define intestinal stem cell differentiation downstream of a FOXO/Notch axis

2019 ◽  
Author(s):  
M.C. Ludikhuize ◽  
M. Meerlo ◽  
M. Pages Gallego ◽  
M. Burgaya Julià ◽  
N.T.B. Nguyen ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Cell Function ◽  
Mitochondrial Fission ◽  
Stem Cell Differentiation ◽  
Notch Signalling ◽  
Intestinal Stem Cell ◽  
Mitochondrial Activity ◽  
Foxo Transcription Factors

SummaryDifferential signalling of the WNT and Notch pathways regulates proliferation and differentiation of Lgr5+ crypt-based columnar cells (CBCs) into all cell lineages of the intestine. We have recently shown that high mitochondrial activity in CBCs is key in maintaining stem cell function. Interestingly, while high mitochondrial activity drives CBCs, it is reduced in the adjacent secretory Paneth cells (PCs). This observation implies that during differentiation towards PCs, CBCs undergo a metabolic rewiring involving downregulation of mitochondrial number and activity, through a hitherto unknown mechanism. Here we demonstrate, using intestinal organoids that FoxO transcription factors and Notch signalling functionally interact in determining CBC cell fate. In agreement with the organoid data, combined Foxo1 and 3 deletion in mice increases PC number in the intestine. Importantly, we show that FOXO and Notch signalling converge onto regulation of mitochondrial fission, which in turn provokes stem cell differentiation into the secretory types; Goblet cells and PCs. Finally, mapping intestinal stem cell differentiation based on pseudotime computation of scRNA-seq data further supports the role of FOXO, Notch and mitochondria in determining secretory differentiation. This shows that mitochondria is not only a discriminatory hallmark of CBCs and PCs, but that its status actively determines lineage commitment during differentiation. Together, our work describes a new signalling-metabolic axis in stem cell differentiation and highlights the importance of mitochondria in determining cell fate.

scholarly journals Inflammation-Mediated Notch Signaling Skews Fanconi Anemia Hematopoietic Stem Cell Differentiation

2013 ◽  
Vol 191 (5) ◽  
pp. 2806-2817 ◽  
Author(s):  
Wei Du ◽  
Surya Amarachintha ◽  
Jared Sipple ◽  
Jonathan Schick ◽  
Kris Steinbrecher ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Notch Signaling ◽  
Hematopoietic Stem Cell ◽  
Fanconi Anemia ◽  
Stem Cell Differentiation ◽  
Hematopoietic Stem ◽  
Hematopoietic Stem Cell Differentiation

scholarly journals Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche

Science ◽  
2018 ◽  
Vol 360 (6396) ◽  
pp. eaan4153 ◽  
Author(s):  
Rumela Chakrabarti ◽  
Toni Celià-Terrassa ◽  
Sushil Kumar ◽  
Xiang Hang ◽  
Yong Wei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammary Gland ◽  
Notch Signaling ◽  
Cross Talk ◽  
Cell Function ◽  
Notch Pathway ◽  
Conditional Deletion ◽  
Mammary Stem ◽  
Cell Niche

The stem cell niche is a specialized environment that dictates stem cell function during development and homeostasis. We show that Dll1, a Notch pathway ligand, is enriched in mammary gland stem cells (MaSCs) and mediates critical interactions with stromal macrophages in the surrounding niche in mouse models. Conditional deletion of Dll1 reduced the number of MaSCs and impaired ductal morphogenesis in the mammary gland. Moreover, MaSC-expressed Dll1 activates Notch signaling in stromal macrophages, increasing their expression of Wnt family ligands such as Wnt3, Wnt10A, and Wnt16, thereby initiating a feedback loop that promotes the function of Dll1-expressing MaSCs. Together, these findings reveal functionally important cross-talk between MaSCs and their macrophageal niche through Dll1-mediated Notch signaling.

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