Premature senescence impairs hematopoietic stem cell function during sickle cell disease in mice and humans (Mouse CITE-Seq)

Curative therapies using autologous genetically modified hematopoietic stem and progenitor cells (HSPCs) are now FDA-approved for sickle cell disease (SCD). However, there are concerns that the pathophysiology of SCD may degrade the quality of HSPCs required for these cellular therapies. We interrogated the phenotype and function of HSPCs in mice and individuals with SCD. We observed elevated cycling, DNA damage, reactive oxygen species, and hallmarks of senescence in bone marrow HSPCs from SCD mice, which correlated with a loss of long-term repopulating HSPCs. Bone marrow HSPCs from individuals with SCD also display hallmarks of senescence and diminished function. Transcriptomic profiling of mouse and human HSPCs revealed reduced expression of genes regulating cell cycle, DNA replication, and DNA repair, consistent with senescence. Treatment of SCD mice with the senolytic, ABT-263 (Navitoclax), increased HSPC frequency, restored HSPC transplantation activity, and decreased numbers of HSPCs with DNA damage. Thus, we demonstrate that stress-associated loss of function in the bone marrow of mice and individuals with SCD is reversible with senolytic therapy. Our work suggests a strategy for improving the function and fidelity of HSPCs collected for autologous gene therapy, which could further improve the efficacy and safety of these curative therapies.