I seek to understand the molecular abnormalities in mesenchymal stem cells (MSC) in terms of differentiation potential, migration and immunomodulatory abilities in the context of systemic lupus erythematosus (SLE). This study is significant because it helps expand understanding about the contribution of MSC to the development of lupus and evaluate the basis for use of autologous versus allogeneic MSC transplantation in treatment of this disease. MSC are considered a highly potential therapeutic tool for lupus and other autoimmune diseases because of their ability to migrate to site of inflammation and exert immunomodulatory effect on immune cells. Literature and preliminary data from my laboratory, however, indicate that MSC derived from the bone marrow (BM) of lupus mice and patients have altered functional profile, which may reduce their immunomodulatory effect in disease. In this study, I will isolate BM-MSC from lupus mouse models and further characterize their functional differences. The three areas to be investigated in this project are: 1. Identify the defects in signaling pathways in BM-MSC from lupus mouse models and investigate their effect on differentiation potential. Preliminary data from my laboratory show that BM-MSC are more prone to differentiate into adipocytes (versus osteoblast). This may contribute to reduced bone mass and density in SLE patients, as well as defects in hematopoietic niche in bone marrow and abnormalities in immune cell types.
I aim to identify specific defects in signaling pathways that control differentiation from BM-MSC. This helps open potential for targeting these specific defects and restoring normal differentiation profile of MSC in lupus. 2. Compare migration ability of BM-MSC from lupus mouse models and normal mice. MSC have the ability to migrate from bone marrow to sites of inflammation by interaction between their surface receptor CXCR4 and SDF-1 signal at those sites. To evaluate whether BM-MSC from lupus models retain full ability to migrate, I will perform in vitro and in vivo migration assay. I will investigate the level of expression of CXCR4 and the activation of corresponding signaling pathway after MSC are exposed to SDF-1 signals. 3. Evaluate immunomodulatory potential of BM-MSC in lupus. MSC are known to affect the proliferation and functions of T-cells, B-cells, dendritic cells (DC), and natural killer (NK) cells to induce a more anti- inflammatory profile. I will investigate the secretion of relevant cytokines from MSC and co-culture MSC with each of these cell types to evaluate the immunomodulatory effects of MSC from lupus models.
Mesenchymal stem cells are being tested as a potential treatment for autoimmune diseases such as systemic lupus erythematosus. This project proposes to investigate cellular and molecular mechanisms underlying abnormalities of mesenchymal stem cells in lupus. It is hoped that the study will help expand understanding of the contribution of mesenchymal stem cells to the development of lupus and form the basis for designing mesenchymal stem cell based therapy for lupus.
