Grant: Project Grant

As we age, our blood-forming stem cells gradually lose their ability to generate a healthy and diverse immune system. In particular, these cells become less capable of producing lymphocytes, the white blood cells that protect us from infections and cancer. This age-related shift contributes to weakened immunity, poor vaccine responses, and a higher risk of blood cancers. Similar damage also occurs when stem cells are grown outside the body for clinical use, limiting the effectiveness of stem cell transplants. Our team discovered UM171, a small molecule that can "rejuvenate" human blood stem cells. UM171 works by removing a molecular brake that normally blocks immune cell development. This brake is formed by a protein complex that silences genes required for healthy immune function. When UM171 removes this brake, stem cells regain their ability to produce immune cells and expand outside the body. Importantly, patients who received UM171-treated stem cells have shown improved immune recovery, including a more diverse and functional immune system. In this project, we aim to understand how UM171 restores immune potential and whether this process can also benefit stem cells from older adults. We will identify the key proteins involved, determine how long the beneficial effects last after treatment, and test whether this strategy can reverse age-related immune decline. By revealing how immune function can be restored at the stem cell level, this research could lead to improved stem cell transplants, better immune recovery after cancer therapy, and new strategies to combat immune aging. Ultimately, our findings may help extend healthy immune function later into life.