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 Unraveling the Control of Cell Cycle Periods during Intestinal Stem Cell Differentiation

2018 ◽  
Vol 115 (11) ◽  
pp. 2250-2258 ◽  
Author(s):  
Richard Ballweg ◽  
Suengwon Lee ◽  
Xiaonan Han ◽  
Philip K. Maini ◽  
Helen Byrne ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Intestinal Stem Cell

scholarly journals Mitochondria Define Intestinal Stem Cell Differentiation Downstream of a FOXO/Notch Axis

2020 ◽  
Vol 32 (5) ◽  
pp. 889-900.e7
Author(s):  
Marlies C. Ludikhuize ◽  
Maaike Meerlo ◽  
Marc Pages Gallego ◽  
Despina Xanthakis ◽  
Mar Burgaya Julià ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Stem Cell Differentiation ◽  
Intestinal Stem Cell

135 MTG16 Plays a Critical Role in Intestinal Stem Cell Differentiation and Injury Responses

2014 ◽  
Vol 146 (5) ◽  
pp. S-37-S-38
Author(s):  
Shenika Poindexter ◽  
Rupesh Chaturvedi ◽  
Xi Chen ◽  
Pauline K. Lund ◽  
Mukul K. Mittal ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Differentiation ◽  
Critical Role ◽  
Stem Cell Differentiation ◽  
Intestinal Stem Cell

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.

Sign in / Sign up

Export Citation Format

Share Document