Session: 501. Hematopoietic Stem and Progenitor Cells and Hematopoiesis: Basic and Translational: Poster II
Hematology Disease Topics & Pathways:
Research, Fundamental Science, Translational Research, Hematopoiesis, Biological Processes
Strikingly, as part of these studies, we discovered that HSCs exhibit a dramatic spike in unfolded protein abundance at birth. This raised the question of whether proteostasis disruption limits the efficacy and regenerative potential of human umbilical cord blood-derived hematopoietic stem and progenitor cells, which are collected immediately after birth. To test this, we fractionated umbilical cord blood-derived CD34+ cells based on unfolded protein content and assessed their function. CD34+ cells with low unfolded protein content had up to 9-fold higher colony-forming efficiency than CD34+ cells with high unfolded protein. Furthermore, CD34+ cells with high unfolded protein content exhibited diminished reconstituting activity in xenotransplantation assays in vivo.
These findings indicate that the HSC proteostasis network undergoes dynamic changes throughout ontogeny and that HSCs depend on distinct age-specific mechanisms to maintain proteostasis throughout life. Stratifying CD34+ cells by variations in proteostasis identifies populations with varied fitness and engraftment potential. As a result, uncovering distinct proteostasis dependencies could offer a unique window for uncovering new therapeutic avenues for enhancing HSC fitness that leverage developmental stage-specific proteostasis programs and reveal proteostasis-based biomarkers as predictors of stem cell quality and transplantation outcomes.
Disclosures: Signer: Vir: Current equity holder in publicly-traded company; Illumina: Current equity holder in publicly-traded company; Syndax: Current equity holder in publicly-traded company; Exact Sciences: Current equity holder in publicly-traded company, Other: Spouse employment.