3062 – SICKLE CELL DISEASE COMPROMISES THE HEMATOPOIETIC STEM CELL BONE MARROW NICHE WITH AGE

• Published in: Experimental hematology 2022, Vol.111, p.S75-S76
• Main Authors: Dabbah, Mahmoud, Barve, Aditya, Kooienga, Emilia, Kelley, Zakiya, Butler, Jason, Derecka, Marta, Freeman, Shanoon McKinney
• Format: Article
• Language: English
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2022.07.118

Sickle cell disease (SCD) is characterized by chronic inflammation caused by red blood cell hemolysis, which can trigger oxidative stress and tissue injury that contribute to disease. Recent studies have shown that SCD pathophysiology reconstituted post-transplant in mouse models disrupts the architecture of bone marrow (BM) sinusoidal endothelium and causes a loss of mesenchymal stromal cells (MSCs). However, the impact of SCD on the ability of MSCs and endothelial cells (ECs) to support hematopoiesis remains unknown. We now report that both sinusoidal and arteriolar MSCs are more abundant in the BM of young SCD patients and a mouse model of SCD, where they also display increased proliferation evident at 2, 6- and 12-months of age. Additionally, 12-month old SCD mice displayed loss of sinusoidal ECs. Murine SCD MSCs displayed decreased CFU-F potential and impaired osteoblast differentiation at 6- and 12-months of age. In ex vivo tri-cultures of primary BM MSCs, ECs and highly purified HSCs, we found that 2, 6, and 12-month old SCD stroma (MSCs and ECs) failed to support WT HSCs relative to control age-matched MSCs and ECs. Phenotypic HSCs isolated from SCD MSCs and EC tri-cultures displayed a loss of CFU potential and transplantation activity. During tri-culture, SCD MSCs, but not SCD ECs, drove increased HSC proliferation, apoptosis, and lymphoid-biased transplantation. Bulk RNA-sequencing of murine SCD MSCs revealed an accelerated aging signature in SCD MSCs relative to controls, as well as perturbed gene expression programs consistent with increased proliferation, loss of extracellular matrix, perturbed secretory activity, impaired immune modulation, and a reduced ability to support HSCs at all ages interrogated. In sum, our data reveals that SCD MSCs are perturbed in young patients and young mice and retain poor HSCs support ability throughout age.