Developmental programming of adult stem cells

PROJECT SUMMARY Early life exposures play a significant role in shaping health and disease susceptibility. Yet, our understanding of the developmental programming of adult stem cells that maintain tissue homeostasis is limited. Mature adult intestinal stem cells (ISCs) sustain continuous life-long adaptations to diet and the intestinal microbial milieu to preserve tissue stability and prevent sequelae leading to diseases such as inflammatory bowel disease (IBD) or sporadic cancer. ISC’s developmental trajectory is influenced early in life by a maternal environment that provides extrinsic patterning cues and nutrients to influence cell, tissue, and system maturation. Despite the fundamental nature of these developmental phases, we do not understand how durable programmable molecular mechanisms are established or how adverse maternal environmental exposure is maintained in a stable and homeostatic manner within ISCs. There is a critical need to establish how the environment contributes to intestinal homeostasis and long-term disease risk. Using genetically engineered mouse and organoid models, this project aims to distinguish ISC developmental programming and determine both early intrinsic adaptations and extrinsic environmental interactions that promote establishment of a stable pre- pathological ISC ground state. Our central hypothesis is that offspring exposure to an obesogenic maternal environment during pre- and postnatal development establishes a maladaptive pre-pathological ground state ab initio. In Aim1 we will characterize the extent of altered ISC changes in offspring exposed to maternal pro- obesity high-fat Western diet (HFD) during pre- and postnatal phases of maternal dependence, and test the duration that these features exist as offspring age. We will further challenge offspring with the reintroduction of the HFD and test for pathological states. In Aim2, we will investigate how lipid metabolism drives ISC- programming by testing for necessity of lipid regulators, Ppar-d and Ppar-a, and for sufficiency with increased PPAR-d activity. In Aim3, we will explore the role that external signaling from the immune system contributes to developmental programming and later risk of disease. We will test the necessity of pro-inflammatory cytokine IL-17 and the influence in tumorigenesis and inflammatory states. In summary, these efforts will enhance our understanding of how developmental programming in early life leads to health and disease disparities as we age.