2010 – THE PROTEOSTASIS NETWORK IS DYNAMICALLY REGULATED THROUGHOUT HEMATOPOIETIC STEM CELL ONTOGENY

Hematopoietic stem cells (HSCs) establish hematopoiesis and maintain regeneration of blood and immune cells to meet shifting demands for blood cell production during development and throughout life. The protein homeostasis (proteostasis) network is uniquely configured in adult HSCs to preserve stem cell fitness and longevity. However, how proteostasis is regulated in developing HSCs is largely unexplored. Here, we comprehensively analyzed proteostasis network activity throughout fetal and neonatal development. Fetal HSCs exhibited up to 7-fold higher protein synthesis rates than their adult counterparts but contained similarly low amounts of unfolded and misfolded proteins as adult HSCs without substantial shifts in protein degradation activity. These data suggested that fetal and adult HSCs utilize distinct mechanisms to preserve proteostasis. We found that fetal HSCs preferentially activated Hsf1, a key proteostasis sensor, and preferentially expressed multiple Hsf1 target genes. Deletion of Hsf1 in the developing hematopoietic system altered HSC ontogeny during the transition from the fetal liver to the bone marrow. Strikingly, HSCs exhibited a dramatic spike in unfolded protein abundance at birth, raising the question of whether proteostasis disruption impairs the function of temporally analogous human umbilical cord blood-derived HSCs. To test this, cord blood CD34+ cells were sorted based on unfolded protein content. Cord blood hematopoietic stem and progenitor cells with low unfolded protein content formed up to 9-fold more colonies than cells with high unfolded protein, which also exhibited diminished reconstituting activity in vivo. Overall, distinct regulation of proteostasis is a key developmental feature of HSCs that could be leveraged to optimize HSC-based therapeutics.