Lupus-Related Gene Found to Induce Stem Cell Dysfunction

Researchers at the University of Florida published in The Journal of Immunology their findings of a lupus-related gene capable of interfering with stem cell differentiation and immunosuppressive action. The study, led by Dr. Laurence Morel, is entitled “The Murine Pbx1-d Lupus Susceptibility Allele Accelerates Mesenchymal Stem Cell Differentiation and Impairs Their Immunosuppressive Function” and was funded by the Lupus Foundation of America.

Systemic lupus erythematosus (SLE) is a severe autoimmune disease in which the body’s own immune system overreacts and attacks healthy joints and organs, resulting in inflammation, pain, disability and often in tissue destruction. The causes underlying the disease are poorly understood, but evidence suggests that it might be caused by defects in specific cells from the bone marrow.

It is known that the bone marrow generates mesenchymal stem cells (MSCs) that are capable of counteracting the effects caused by the overreaction of the immune system. It is thought that individuals with lupus often have MSCs that do not function properly, possibly contributing to disease progression. Therefore, MSCs from SLE patients should not be considered or used in self (autologous) mesenchymal bone marrow stem cell transplants, a therapy often employed in individuals with severe, life-threatening cases of lupus.

The aim of this study was to determine whether mesenchymal stem cells carrying a gene known to be associated to increased lupus susceptibility — the Pbx1 gene — would be malfunctioning cells, without therapeutic immunosuppressive action. The Pbx1 gene has been previously shown to be involved in the maintenance of stem cell self-renewal, including of MSCs, and to stimulate immune cells into a more aggressive mode in both lupus mice models and SLE patients.

Using mice models, the researchers found that the expression of Pbx1in MSCs induced a significant increase in the expression of genes associated with cell differentiation. Pbx1 was also found to induce the expression of genes associated with an enhanced innate immunity and inflammation in MSCs.

The research team concluded that Pbx1 expression impairs the function of MSCs, which may ultimately contribute to lupus pathogenesis due to a defective immunosuppression and the induction of a proinflammatory environment.

This is the first study to establish that a lupus-related gene can affect mesenchymal stem cells. “This study may contribute to advancing mesenchymal stem cells cellular therapies in lupus, not only by providing a better understanding of how they work, but also by genetic screening to identify optimal mesenchymal stem cells to be used for therapy,” explained Dr. Morel in a news release. In addition, this study may help clinicians to predict in the future who might benefit from stem cell therapy.

“As a next step, we are seeking additional funding to understand the mechanism by which Pbx1 regulates the function of mesenchymal stem cells in mice and humans and to test how to restore the normal functions of mouse and human lupus mesenchymal stem cells to be used in cellular therapy.”