Proteostasis Remodeling Across Development Defines Fetal, Neonatal, and Adult Hematopoietic Stem Cell States

ABSTRACT Hematopoietic stem cells (HSCs) must preserve protein homeostasis (proteostasis) despite dramatic changes in proliferative and biosynthetic demands during development, yet how proteostasis is regulated across these transitions is poorly understood. Here, we show that fetal and neonatal HSCs operate through distinct, stage-specific proteostasis programs that differ fundamentally from those in adulthood. Using quantitative in vivo assays spanning embryonic through adult stages, we uncover an unanticipated decoupling between protein synthesis and protein quality control during development, revealing that fetal and neonatal HSCs employ specialized mechanisms to safeguard proteome integrity under developmental stress. Developing HSCs experience a distinctive proteostasis landscape characterized by elevated protein synthesis, increased unfolded protein burden, and selective engagement of stress-buffering and protein degradation pathways that are largely dispensable in young adult HSCs. Disruption of these pathways compromises early life HSC function and long-term fitness, establishing proteostasis control as a key regulator of stem cell maturation. These findings define previously unrecognized mechanisms by which HSCs manage the proteome during early life and reveal fundamental principles governing stem cell proteostasis across ontogeny.