Patients with muscular dystrophy suffer debilitating muscle loss that gets worse as they age. As the disease progresses, resident stem cells in a patient’s muscle tissue have to work extra hard trying to replace the diseased muscle. Over time, this special population of stem cells gets exhausted as they constantly proliferate (make more stem cells) and differentiate (specialize into new muscle cells).
Dr. Pier Lorenzo Puri, associate professor at Sanford-Burnham and Italy’s Dulbecco Telethon Institute, and colleagues are figuring out ways to keep the muscle stem cell pool fresh and ready to regenerate injured or diseased muscle. In a study published today in the journal Cell Stem Cell, they uncover the molecular messengers that translate inflammatory signals into the genetic changes that tell muscle stem cells to differentiate. These findings give the scientists a target to artificially dial the stem cell population up or down, a potential treatment that could boost muscle regeneration in muscular dystrophy patients.
“Our mission is to improve the lives of these patients and extend their lives until they can benefit from a cure 20 years from now,” says Dr. Puri, a medical doctor who has worked with many muscular dystrophy patients throughout his career.
Diseased or injured muscle becomes inflamed as cells and molecules flood the area to control the damage and begin repairs. Dr. Puri’s latest findings center around an inflammatory molecule called tumor necrosis factor (TNF) and a messenger molecule it talks to, called p38 alpha MAPK. Essentially, p38 alpha MAPK responds to inflammation by determining whether stem cells loitering in adult muscle tissue keep refreshing the pool of stem cells, or differentiate into functioning muscle cells.
Armed with this information, the research team used antibodies directed against TNF to block p38 alpha MAPK activity specifically in stem cells, a move that produced more stem cells. Anti-TNF antibodies could be used to generate more muscle stem cells in muscular dystrophy patients.
Once more muscle stem cells are generated, they can be induced to differentiate into functioning muscle cells. According to Dr. Puri, “the effect of anti-TNF treatment is reversible, so withdrawing the drug could then force the expanded population of stem cells to repopulate muscle cells.”
What’s more, since anti-TNF is already FDA-approved to treat rheumatoid arthritis and other autoimmune diseases, Dr. Puri hopes it will be more likely to benefit the current generation of muscular dystrophy patients – people who can’t wait decades for new drugs to be developed and approved.
“There’s an emotional charge in my lab,” Dr. Puri says. “We know there are children waiting for us to do our jobs, and when we work we are targeting those faces, those smiles.”