Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans.

Abstract

Sickle cell disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases the risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, likely because of chronic stress on bone marrow. To investigate this further, we interrogated bone marrow hematopoietic stem and progenitor cells (HSPCs) from mice and individuals with SCD and observed molecular signatures of chronic cellular stress including oxidative stress, DNA damage, and hallmarks of senescence. Consistent with these findings, SCD HSPCs displayed transcriptomic dysregulation of senescence-associated molecular programs and diminished mitogen response with prolonged cell cycle kinetics during time-lapse live cell imaging. SCD mice displayed a marked loss of immunophenotypic bone marrow HSPCs by flow cytometry and functional blood repopulating HSPCs in transplantation studies, whereas human SCD bone marrow HSPCs exhibited poor ex vivo hematopoietic colony-forming ability, and these phenotypes were reversed after senescence-targeting therapy with either ABT-263 (navitoclax) or the combination of dasatinib and quercetin. Thus, treatment with senescence-targeting therapy improves bone marrow HSPC function in vivo in mice and ex vivo in cells from individuals with SCD and could represent a possible strategy to improve HSPC health, promote manufacture of high-quality bespoke clinical products, and potentially enhance the safety of potentially curative gene therapies using autologous HSPCs from individuals with SCD.