Phase separation of Rbpms sequesters translation elongation machinery to preserve hematopoietic stem cell function.

The mechanisms by which hematopoietic stem cells (HSCs) maintain long-term (LT) hematopoietic capacity and transition from quiescence remain incompletely understood, limiting their in vitro expansion and applications. Accumulating evidence underscores the importance of maintaining a low protein synthesis rate for HSC function, yet the underlying mechanisms remain elusive. Here, we identified ribosome-associated proteins specifically enriched in HSCs and multipotent progenitors (MPPs) and found that RNA-binding protein gene with multiple splicing (Rbpms) is required for sustaining low protein synthesis rates in HSCs. Rbpms forms biomolecular condensates that sequester translation elongation factors and protein-folding chaperones from ribosomes, slowing translation elongation and ensuring proper protein folding in HSCs. Rbpms deletion led to accelerated protein synthesis, accumulation of misfolded proteins in HSCs, impaired LT hematopoietic reconstitution capacity, accompanied by aberrant exit from quiescence. Our findings unveil a unique mechanism of translation elongation regulation in HSCs and highlight significance of spatial compartmentalization and translational control in HSCs.