Consortium on Intestinal Regeneration and Fetal Reversion: from Atlas to Therapy

ABSTRACT Fetal reversion is a novel regenerative phenomenon in which cells of the intestinal epithelium respond to damage by downregulating the normal gene expression program observed during homeostasis and by acquiring a fetal- like transcriptional state that promotes cell proliferation and intestinal repair. Fetal reversion has been observed

in different intestinal injury models in the mouse, including damage from parasitic or viral infection, radiation, and chemical insults. It is unknown if fetal reversion is a universal property of intestinal healing or if it occurs only during certain types of repair. Recent evidence indicates that this phenomenon may also occur in the human

intestine; however, this has also not been interrogated in a systematic way. This project will create a unique large-scale research resource – an atlas of intestinal injury across multiple species (mouse, human) and damage models that contains comprehensive single cell multiomic datasets of regulatory and transcriptional dynamics during intestinal repair after injury. The atlas will be a tool for future

hypothesis generation for functional studies and will be an important community-wide resource available to the entire scientific community. Genes and pathways essential for fetal reversion, and for any other common intestinal regeneration programs, will be identified using atlas data. Functional studies to explore pathways and

genes will be conducted in mouse models through gain- and loss-of-function experiments and will be interrogated in the human context using intestinal organoids as a model system. A high-throughput drug screening assay will be used to identify compounds that induce fetal reversion, and top compounds identified will be assessed for

their ability to induce the fetal reversion state through transcriptomic and epigenomic assays, and to enhance organoid-engraftment and injury repair in vivo through transplantation assays. This project will create a multi-species injury-repair atlas and comprehensively characterize different modes of

intestinal regeneration, including fetal reversion, providing an unprecedented understanding of intestinal injury- repair. All data, analyses, methods, models and screening protocols will be shared with the research community for exploration and further analysis following established sharing models. The studies proposed here will identify

common and unique regenerative programs that are active in different injury contexts, creating a paradigm shift in our understanding of gut repair, and laying the foundation for new fields of research and therapeutics.