Highlights of 2 critical determinants (epigenetic and metabolic) for achieving optimal expansion of functional HSCs. (A) UM171-mediated CRL3^KBTBD4 potentiation preserves HSCs epigenetic signature through CoREST1 degradation (upper panel) and restrain excessive HSC activation through reduction of MYC transcriptional activity (lower panel). (B) CoREST1 and MYC activity indexes may serve as a rheostat, controlling the balance between latent and primed HSCs thus preventing their functional decline upon ex vivo culture.