N1-acetylspermidine is a determinant of hair follicle stem cell fate.

Kira Allmeroth,Christine S Kim,Maxime J Derisbourg,Sara A Wickström,Christian Latza,Andromachi Pouikli,Peter Tessarz,Carlos Andrés Chacón-Martínez,Adam Antebi,Martin S Denzel,Andrea Annibal,Janis Koester

doi:10.1242/jcs.252767

Abstract

ABSTRACTStem cell differentiation is accompanied by increased mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine and spermine, which are essential for cell growth and stem cell maintenance. However, the role of polyamines as endogenous effectors of stem cell fate and whether they act through translational control remains obscure. Here, we investigate the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. Compared to progenitor cells, HFSCs showed lower translation rates, correlating with reduced polyamine levels. Surprisingly, overall polyamine depletion decreased translation but did not affect cell fate. In contrast, specific depletion of natural polyamines mediated by spermidine/spermine N1-acetyltransferase (SSAT; also known as SAT1) activation did not reduce translation but enhanced stemness. These results suggest a translation-independent role of polyamines in cell fate regulation. Indeed, we identified N1-acetylspermidine as a determinant of cell fate that acted through increasing self-renewal, and observed elevated N1-acetylspermidine levels upon depilation-mediated HFSC proliferation and differentiation in vivo. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions.This article has an associated First Person interview with the first author of the paper.

Highlights

MRNA translation is one of the most complex and energyconsuming cellular processes (Roux and Topisirovic, 2018)
Low translation rates and enhanced protein quality control mark the hair follicle stem cell (HFSC) state in 3D–3C organoids Various types of stem cells display lower translation rates than their differentiated counterparts (Baser et al, 2019; Sampath et al, 2008; Signer et al, 2014; Zismanov et al, 2016). This concept applies to the epidermis – HFSCs have lower protein synthesis rates than committed cells in vivo (Blanco et al, 2016)
To test whether isolated HFSCs maintain low translation, we sorted freshly prepared mouse epidermal cells using three different markers (Fig. 1A) – α6 integrin, which is expressed in all progenitors both in the interfollicular epidermis (IFE) and the hair follicle (HF) (Li et al, 1998; Sonnenberg et al, 1991); the hematopoietic stem cell marker CD34, which marks the bulge stem cells of the HF (Trempus et al, 2003); stem cell antigen-1 (Sca1; known as LY6A), which is expressed in the infundibulum (IFD) region of the HF and in the basal layer of the epidermis (Jensen et al, 2008)

Summary

Introduction

MRNA translation is one of the most complex and energyconsuming cellular processes (Roux and Topisirovic, 2018). The regulation of mRNA translation has been implicated in early cell fate transitions (Ingolia et al, 2011; Kristensen et al, 2013; Lu et al, 2009). Several studies in both embryonic and somatic stem cells demonstrate that global translation is suppressed in stem cells to retain them in an undifferentiated state, whereas translation is increased in progenitor cells upon differentiation (Baser et al, 2019; Sampath et al, 2008; Signer et al, 2014; Zismanov et al, 2016)

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