Polyamine-controlled proliferation and protein biosynthesis are independent determinants of hair follicle stem cell fate

Stem cell differentiation is accompanied by an increase in mRNA translation. The rate of protein biosynthesis is influenced by the polyamines putrescine, spermidine, and spermine that 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 investigated the function of polyamines in stem cell fate decisions using hair follicle stem cell (HFSC) organoids. HFSCs showed lower translation rates 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, increasing proliferation without reducing translation. Overall, this study delineates the diverse routes of polyamine metabolism-mediated regulation of stem cell fate decisions. Key PointsO_LILow mRNA translation rates characterize hair follicle stem cell (HFSC) state C_LIO_LIDepletion of natural polyamines enriches HFSCs via reduced translation C_LIO_LIN1-acetylspermidine promotes HFSC state without reducing translation C_LIO_LIN1-acetylspermidine expands the stem cell pool through elevated proliferation C_LI