Directing Cell Fate Along the Intestinal Enteroendocrine Lineage

Project Summary/Abstract Body weight and energy balance are tightly regulated by complex hormonal interplay of the gut and the central nervous system to control appetite and energy expenditure. Gut hormone signals from intestinal enteroendocrine cells (EECs) can either be orexigenic, enhancing hunger and promoting food intake, or anorexigenic, promoting satiety to inhibit food intake. Gut hormonal signaling dysfunction is implicated in obesity, a disease with enormous public health burden in the US and worldwide. Understanding this dysfunction will provide critical insight to the pathogenesis of obesity and its co-morbidities, and ultimately provide novel avenues to ameliorate it. The gastrointestinal tract is the largest endocrine organ and harbors the greatest number of hormone- producing cells in the body. This system holds vast potential for our ability to understand, and possibly manipulate, hormone signaling dysfunction. However, our understanding of hormones and the EECs that produce them remain poor. The intestinal epithelium is a rapidly self-renewing tissue and contains rare, heterogeneous EECs scattered throughout that produce a variety of hormones. EECs are generated from the sequential differentiation of multi-potent actively proliferating intestinal stem cells residing in the intestinal crypts that continuously produce replacement cells to support cellular turnover of the epithelium. The evolving understanding of cellular lineage hierarchy upon intestinal stem cell differentiation suggest that, rather than exogenous hormone delivery to patients, we may be able to pharmacologically manipulate the intestinal stem/progenitor cell state to guide their in vivo lineage output toward production of distinct EEC subtypes or to control the release of their hormone products for therapeutic applications. Here we will define the intestinal EEC lineage at single-cell resolution, including its diverse and discrete subtypes, and study how they are inter-related, to exponentially advance existing knowledge of these cells. We will also identify and functionally dissect the pathways that enforce specific EEC subtypes that would be therapeutically beneficial. This a high-risk/high-reward proposal with potential for direct translation to treatment of obesity and diabetes, which are global-scale human diseases.