The UNC Provost’s Office awarded Heather McCauley a Junior Faculty Development Award to create a new humanized mouse model that more closely replicates complex epithelial and immune cell dynamics in the gut.
Lining the intestines are rare hormone-producing cells called enteroendocrine cells that sense nutrients, gut microbes, and metabolites in the food we eat. These cells can even detect physical cues like how much our intestines stretch when we consume a meal. In response to these changes, enteroendocrine cells secrete a slew of hormonal peptides, metabolites, neurotransmitters, and cytokines throughout the body to prepare it for an influx of nutrients. But enteroendocrine cells may also play a central yet elusive role in gastrointestinal health.
Enteroendocrine cells are often dysregulated in many metabolic and gastrointestinal disorders but normalize with dietary changes. This leads many scientists to wonder if abnormalities in these cells are a contributing cause or consequence of gastrointestinal dysfunction. Heather McCauley, an assistant professor in the Department of Cell Biology and Physiology at the University of North Carolina at Chapel Hill recently received an R.J. Reynolds Junior Faculty Development Award from the Provost’s Office to develop a powerful new humanized mouse model that more closely replicates intestinal physiology and function to help answer this question.
McCauley hypothesizes that enteroendocrine cells play a causative role in metabolic and gastrointestinal diseases by serving as the mechanistic links between diet, dysbiosis, and gut inflammation. “We anticipate that targeting enteroendocrine cells through dietary interventions or pharmacology may be an underappreciated avenue for prevention or treatment of all metabolic and inflammatory diseases with dietary risk,” said McCauley.
It is well known that enteroendocrine cells regulate their epithelial cell neighbors in the gut. McCauley proposes that enteroendocrine signaling may also regulate neurons, fibroblasts, and immune cells underlying the intestinal epithelium that are too far away to detect nutrient intake. If enteroendocrine signaling becomes dysregulated, immune cells in these areas may not receive the key messages needed to maintain gut health, resulting in gut inflammation.
The problem is that scientists have been unable to comprehensively replicate human immune cell dynamics in mouse models of gastrointestinal disease. Current research strategies are limited to in vitro modeling using human pluripotential stem cell-derived organoids (HIOs), which do not fully capture the complex multi-cell signaling landscape of in vivo gut physiology.
To solve this problem, McCauley’s team plans to develop a new mouse model with a humanized immune system. They will then engraft HIOs with and without enteroendocrine cells into the mice. “This Development Award will enable our lab to develop this humanized mouse model and subsequent transplantation of HIOs to determine the impact of enteroendocrine cells on immune cell development, recruitment, and function in response to [gut] cues,” said McCauley.
Written by Tiffany Garbutt, PhD