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Effect of N1-acetylspermidine treatment on the translatome of hair follicle stem cell organoid cultures

ABSTRACT: Stem cell differentiation has been shown to involve an increase in mRNA translation. Amongst others, the rate of translation is influenced by availability of the natural polyamines putrescine, spermidine, and spermine that are essential for cell growth and modulate stem cell maintenance. However, the link between polyamines and translation in cell fate decisions remains obscure. Here, we used hair follicle stem cell (HFSC) organoids to study the role of polyamines as key regulators of mRNA translation in stem cell fate decisions. HFSCs showed lower translation and reduced polyamine levels than progenitor cells. Surprisingly, we found that reduced translation achieved by changed polyamine availability and stemness do not correlate in the organoids. We identified N1-acetylspermidine as regulator of cell fate decisions. To investigate the effect on translation upon N1-AcSpd supplementation, we performed ribosome foot pronting. We confirmed the increase in proliferation identified by 3'RNA-sequencing on the translatome level. N1-AcSpd treatment partially aligns the translatome of progenitor cells to that of HFSCs. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions.

ORGANISM(S): Mus musculus

PROVIDER: GSE164806 | GEO | 2021/04/23

REPOSITORIES: GEO

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Effect of N1-acetylspermidine treatment on hair follicle stem cell organoid cultures

Project description:Stem cell differentiation has been shown to involve an increase in mRNA translation. Amongst others, the rate of translation is influenced by availability of the natural polyamines putrescine, spermidine, and spermine that are essential for cell growth and modulate stem cell maintenance. However, the link between polyamines and translation in cell fate decisions remains obscure. Here, we used hair follicle stem cell (HFSC) organoids to study the role of polyamines as key regulators of mRNA translation in stem cell fate decisions. HFSCs showed lower translation than progenitor cells, and a forced suppression of translation by direct targeting of the ribosome or through specific depletion of natural polyamines elevated stemness. In addition, we identified N1-acetylspermidine as a novel parallel regulator of cell fate decisions. To identify the molecular mechanism by which N1-AcSpd supplementation promotes stemness, we performed RNA-sequencing. We unravel an increase in proliferation. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions.

2021-04-27 | GSE149704 | GEO

Differential effects of polyamine depletion by DENSpm and DFMO on beta cell stress reponses and type 1 diabetes outcomes in mice

Project description:Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is currently being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA sequencing analysis, however, suggests that the cellular reponses to DENSpm and DFMO differ, with the two sharing similar effects on cellular proliferation, but the latter showing greater effects on mRNA translation and protein folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm administration did not prevent or delay diabetes outcome, but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In non-obese diabetic (NOD) mice, short-term DENSpm administration resulted in slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

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Polyamines induce the glutamate decarboxylase acid response system by increasing the level of the σ38 subunit (RpoS) of Escherichia coli RNA polymerase via gadE regulon

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