Senolytics Restore Hematopoietic Stem Cells Function in Sickle Cell Disease
Aditya BarveiD, Adam B. CornwelliD, Pramika Sriram, Oleg V. KopyoviD, Preeti DabasiD, Emilia KooiengaiD, Zakiya KelleyiD, James D. JohnsoniD, Jacquelyn MyersiD, Esther A. ObengiD, Guolian KangiD, Yunusa OlufadiiD, Terri L. CainiD, Lindsay Jones TalbotiD, David D. SpenceiD, Mauricio CortesiD, Sam Miller, Dirk LoeffleriD, Akshay SharmaiD, Shannon McKinney‐FreemaniD
Abstract
Sickle Cell Disease (SCD) is a blood disorder affecting millions worldwide. Emerging evidence reveals that SCD pathophysiology increases risk of myeloid malignancies and hematopoietic stem cell (HSC) dysfunction, possibly due to pathological stress on bone marrow. To investigate this further, we interrogated mice and individuals with SCD and observed extended cell cycle times, oxidative stress, DNA damage, senescence, and dysregulation of molecular programs associated with these processes in bone marrow hematopoietic stem and progenitor cells (HSPCs). Human SCD HSPCs displayed poor hematopoietic potential ex vivo. SCD mice displayed a dramatic loss of transplantable bone marrow HSPCs, which was reversed upon treatment of SCD mice with the senolytic agent, ABT-263 (navitoclax). Thus, senolytics restore bone marrow function during SCD in mice and represent a novel strategy to improve bone marrow health in individuals with SCD and improve the safety of potentially curative gene therapies that utilize autologous HSPCs from individuals with SCD.
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