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MicroRNAs selectively protect hub cells of the germline stem cell niche from apoptosis.

ABSTRACT: Genotoxic stress such as irradiation causes a temporary halt in tissue regeneration. The ability to regain regeneration depends on the type of cells that survived the assault. Previous studies showed that this propensity is usually held by the tissue-specific stem cells. However, stem cells cannot maintain their unique properties without the support of their surrounding niche cells. In this study, we show that exposure of Drosophila melanogaster to extremely high levels of irradiation temporarily arrests spermatogenesis and kills half of the stem cells. In marked contrast, the hub cells that constitute a major component of the niche remain completely intact. We further show that this atypical resistance to cell death relies on the expression of certain antiapoptotic microRNAs (miRNAs) that are selectively expressed in the hub and keep the cells inert to apoptotic stress signals. We propose that at the tissue level, protection of a specific group of niche cells from apoptosis underlies ongoing stem cell turnover and tissue regeneration.

SUBMITTER: Volin M

PROVIDER: S-EPMC6219711 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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microRNAs selectively protect hub cells of the germline stem cell niche from apoptosis.

Volin Marina M Zohar-Fux Maayan M Gonen Oren O Porat-Kuperstein Lilach L Toledano Hila H

The Journal of cell biology 20180809 11

Genotoxic stress such as irradiation causes a temporary halt in tissue regeneration. The ability to regain regeneration depends on the type of cells that survived the assault. Previous studies showed that this propensity is usually held by the tissue-specific stem cells. However, stem cells cannot maintain their unique properties without the support of their surrounding niche cells. In this study, we show that exposure of <i>Drosophila melanogaster</i> to extremely high levels of irradiation tem ...[more]

PMID: 30093492

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Project description:Background & aimsThe intestinal stem cell niche is exquisitely sensitive to changes in diet, with high-fat diet, caloric restriction, and fasting resulting in altered crypt metabolism and intestinal stem cell function. Unlike cells on the villus, cells in the crypt are not immediately exposed to the dynamically changing contents of the lumen. We hypothesized that enteroendocrine cells (EECs), which sense environmental cues and in response release hormones and metabolites, are essential for relaying the luminal and nutritional status of the animal to cells deep in the crypt.MethodsWe used the tamoxifen-inducible VillinCreERT2 mouse model to deplete EECs (Neurog3fl/fl) from adult intestinal epithelium and we generated human intestinal organoids from wild-type and NEUROGENIN 3 (NEUROG3)-null human pluripotent stem cells. We used indirect calorimetry, 1H-Nuclear Magnetic Resonance (NMR) metabolomics, mitochondrial live imaging, and the Seahorse bioanalyzer (Agilent Technologies) to assess metabolism. Intestinal stem cell activity was measured by proliferation and enteroid-forming capacity. Transcriptional changes were assessed using 10x Genomics single-cell sequencing.ResultsLoss of EECs resulted in increased energy expenditure in mice, an abundance of active mitochondria, and a shift of crypt metabolism to fatty acid oxidation. Crypts from mouse and human intestinal organoids lacking EECs displayed increased intestinal stem cell activity and failed to activate phosphorylation of downstream target S6 kinase ribosomal protein, a marker for activity of the master metabolic regulator mammalian target of rapamycin (mTOR). These phenotypes were similar to those observed when control mice were deprived of nutrients.ConclusionsEECs are essential regulators of crypt metabolism. Depletion of EECs recapitulated a fasting metabolic phenotype despite normal levels of ingested nutrients. These data suggest that EECs are required to relay nutritional information to the stem cell niche and are essential regulators of intestinal metabolism.

Dataset Information

MicroRNAs selectively protect hub cells of the germline stem cell niche from apoptosis.

Publications

microRNAs selectively protect hub cells of the germline stem cell niche from apoptosis.

Similar Datasets

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