Wednesday, February 5, 2025
2/5/2025
Project Summary The enteric nervous system (ENS) is of fundamental importance to human health through its regulation of all aspects of gastrointestinal (GI) function, most notably gut motility. Congenital or acquired abnormalities of the ENS consequently can lead to serious functional GI disorders, including esophageal achalasia, gastroparesis, intestinal pseudo-obstruction, irritable bowel syndrome, Hirschsprung disease, and slow transit constipation. The adult intestine is known to possess neuronal progenitors that can be utilized for regenerative cell therapy to treat these neurointestinal diseases. However, to be able to stimulate endogenous enteric neurogenesis in the adult intestine, or to improve current methods for culturing and expanding neuronal progenitors in a dish, we need to understand the mechanisms that regulate the neurogenic response in the gut. In our current R01, we have shown that a subset of enteric glial cells, highly enriched within the myenteric ganglia, possesses a gene expression program and chromatin state predictive of neurogenic potential. These cells are capable of undergoing rapid neuronal differentiation in response to specific stimuli, such as intestinal inflammation. The overall objective of the current proposal is to define the cellular, molecular, and epigenetic signals that activate this inflammatory-mediated neurogenic response in glia. Based on our preliminary studies, we propose the following specific aims: (1) determine the role of muscularis macrophages and their inflammatory products in promoting enteric neurogenesis; (2) investigate the role of Sox2 and Sox10 transcription factors in preventing neuronal differentiation of enteric glia; and (3) characterize the phenotypic diversity and function of newly born glial-derived neurons. This proposal is innovative in testing an immune-mediated mechanism for postnatal enteric neurogenesis and does so utilizing state-of-the-art techniques, including CUT&RUN epigenomic profiling, AAV-based gene silencing in vivo, neurosphere transplantation, and isolation and culture of muscularis macrophages. The team provides expertise in ENS development, enteric neuronal stem cell biology, ENS cell therapy, intestinal inflammation, bioinformatics, and clinical neurogastroenterology. Successful completion of the proposed experiments will significantly enhance our understanding of the mechanisms underlying neurogenesis in the adult intestine, identify new targets for pharmacotherapies that can modulate enteric neurogenesis in vivo, and improve our ability to expand enteric neuronal progenitors in vitro for cell therapy applications, including the development of cell transplantation for the treatment of Hirschsprung disease and other neurointestinal diseases.
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