Murine bone marrow mesenchymal stromal cells have reduced hematopoietic maintenance ability in sickle cell disease.

Sickle Cell Disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contributes to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease but their functionality in SCD remains unclear. We identified for the first time murine SCD MSCs to have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo as manifested by increased HSC mobilization and decreased HSC engraftment following transplant. Activation of TLR4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.