Penn Dental Medicine Study Shows How Stem Cell Therapy Protects Bone in Lupus

Philadelphia, USA – Individuals with lupus, an autoimmune disease, suffer from fatigue, joint pain and swelling and also have a markedly increased risk of developing osteoporosis. Clinical trials have shown that a mesenchymal stem cell transplant can greatly improve the condition of lupus patients, yet it has not been clear why this treatment works so well.

Now, Penn Dental Medicine researcher Songtao Shi, chair and professor of Anatomy & Cell Biology, and his colleagues have puzzled out a mechanism by which stem cell transplantation may help preserve bone in an animal model of lupus. In a paper published in Cell Metabolism, they show that the transplanted cells provide a source of a key protein called Fas, which improves the function of bone marrow stem cells through a multi-step, epigenetic effect. The work has implications for potential therapeutic strategies for lupus, as well as other diseases for which stem cell transplantation have shown promise.

“When we used transplanted stem cells for these diseases, we didn’t know exactly what they were doing, but saw that they were very effective,” said Shi. “Now we’ve seen in a model of lupus that bone-forming mesenchymal stem cell function was rescued by a mechanism that was totally unexpected.”

Shi and his colleagues had earlier shown that mesenchymal stem cells can be used to treat various autoimmune conditions in animal models. The success was welcome, but they didn’t quite understand why it was so successful. They began to suspect an epigenetic mechanism at work that could permanently recalibrate how the recipient’s genes were being regulated, switching them from a pathogenic to a normal state.

Pursuing that possibility, their experiments would piece together the pathway of the genes to discover that the lupus mice had a malfunctioning Fas protein that prevented their bone marrow mesenchymal stem cells from releasing a molecule needed for normal differentiation/bone formation.

When a stem cell infusion was introduced, however, the donated cells secreted microvesicles containing normal versions of Fas that could be reused by the diseased cells, restoring their ability to self-renew and differentiate and promoting bone formation.

“The cells themselves don’t produce Fas, but they can use the components of the donor stem cells to rescue their function,” said Shi.

To see if this process is common across different conditions, Shi is now exploring the mechanisms by which stem cell therapies reap benefits in other models of disease.