Bone marrow stem cell niche dysfunction in human SLE
The bone marrow (BM) stroma consists of cells providing a microenvironment for hematopoiesis, which are replenished by self-renewing mesenchymal stem cells (MSCs). Normal hematopoiesis depends on the healthy BM microenvironment. Hematopoietic stem cells (HSCs) are supported by MSCs occupying two distinct BM niches, endosteal and vascular, which regulate HSC quiescence, self-renewal and differentiation. MSC dysfunction is reported in SLE, but the causes are largely unknown. We found that local TNFa production is associated with niche dysfunction and HSC death in lupus BM. This project addresses the hypothesis that local production of proinflammatory cytokines in SLE BM causes MSC niche dysfunction and decreased HSC survival, resulting in anemia/cytopenias. We will 1) morphologically characterize stem cell niches in SLE patients* BM looking for evidence of MSC/niche dysfunction; 2) compare niche formation/function in novel 3D culture systems using lupus vs, control MSCs; and 3) determine whether MSC exposure to cytokines produced in SLE BM directly causes niche dysfunction. Hematological abnormalities occur in 70-80% of lupus patients, contributing to fatigue and other clinical manifestations. Our studies may uncover cytokines like TNFa responsible for BM niche dysfunction, leading to new strategies to reduce fatigue and prevent stem-cell transplant-related mortality in SLE patients.