Tuning SOX10 Dosage in Stem Cell Therapies for Hirschsprung Disease
Hirschsprung disease is a life-threatening childhood condition in which neurons that control movement of waste through the intestine fail to develop, leading to severe constipation, swelling, and infections. Currently, Hirschsprung is treated by removing part of the intestine, but many children continue to experience bowel issues even after surgery. A promising new approach is to derive human stem cells from the patient or a donor, guide them into neuron precursor cells in a dish, and transplant them into the intestine. This could restart proper bowel function by replacing lost neurons, but so far progress has been limited by a major challenge: the same cells must both migrate long distances to spread throughout the gut and mature into functional neurons, but maturing into neurons (differentiation) reduces their ability to migrate.
Our research focuses on overcoming the migration–differentiation tradeoff by modulating transcription factors, master proteins that act as switches to guide cells between alternative states. Our preliminary work has developed a new way to control the levels of the transcription factor SOX10, which genetic studies have shown to be critical for gut neuron development and Hirschsprung disease. We can control SOX10 levels within stem cell–derived neuron precursor cells, the same type of cells that would be used for therapy, and test how this affects migration and differentiation when these cells are transplanted into gut tissue.
In this project, we will first define how SOX10 dosage influences the molecular circuits controlling cell migration and neuronal differentiation. We will then test whether timed adjustment of SOX10 levels improves colonization of intestinal tissue, by maintaining higher levels during early migration and lowering them later to trigger neuron formation.
This work addresses the root cause of Hirschsprung disease, the absence of gut neurons, and seeks to restore function by replacing them in a controlled way. If successful, it could move treatment beyond surgery and improve the lives of children affected by this devastating disorder. The strategies developed here may also apply to other childhood conditions where stem cell therapies are being explored.