2014 Anemia, New Treatments, Human Lupus Biology
Bone marrow stem cell niche dysfunction in human SLE
The study and what it means to patients
Dr. Lijun Yang is asking whether a low blood cell count (anemia) in lupus can be reversed by an arthritis drug that prevents damage to essential blood-cell producing stem cells in the bone marrow.
“We will study the role of immune system molecules called cytokines, particularly tumor necrosis factor (TNF), in the production of blood cells in the bone marrow of lupus patients. In addition, we will look at the role of TNF in the laboratory in conditions that mimic the structure of the bone marrow in real life. If we confirm that TNF is involved, it may be possible to use drugs already used to treat arthritis called TNF inhibitors to block these effects. Our studies will provide a better understanding of the causes of anemia and fatigue in lupus.”
The bone marrow (BM) stroma consists of cells that provide a microenvironment for hematopoiesis, which are replenished by self-renewing mesenchymal stem cells (MSCs). Normal hematopoiesis depends on a healthy BM microenvironment. Hematopoietic stem cells (HSCs) are supported by MSCs occupying two distinct BM niches, the endosteal and vascular niches, which regulate HSC quiescence, self-renewal and differentiation. MSC dysfunction has been reported in SLE, but the causes are largely unknown. We have found that local production of TNF 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 the BM of SLE patients, 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 show that cytokines like TNF are responsible for BM niche dysfunction, leading to new strategies to reduce fatigue and prevent stem-cell transplant-related mortality in SLE patients.