Exploring the dynamics of the gastrointestinal tract using shed cell and spatial transcriptomics

The gastrointestinal (GI) tract undergoes significant changes during post-natal development and in response to various diseases. Single-cell atlases are static and therefore fail to capture the dynamic changes occurring within the GI tract. We have devised a method to transcriptomically profile cells that are naturally shed into the GI tract. Contrary to earlier beliefs, we found that shed cells remain viable and can robustly be measured in fecal samples. Shed cell transcriptomics enables non-invasive tracking of cellular states throughout development and disease progression. Moreover, discrepancies between transcriptomic profiles of shed cells and tissues can identify which cell types are preferentially shed or retained, revealing cell turnover patterns. Our objective is to combine shed-cell and spatial transcriptomics to achieve basic and biomedical discoveries that were not possible before: 1. To study the developmental changes in the neonatal human GI tract. This will include longitudinal acquisition and in-depth analysis of shed cell transcriptomic and proteomic data in stool samples obtained from babies. 2. To characterize turnover of cells in colorectal cancer (CRC). We will combine shed cell transcriptomics in stool and blood with spatial transcriptomics of tumor biopsies to spatially map the cancer cells that resist death/shedding and examine their interactions within the tumor microenvironment. 3. To investigate cellular dynamics and tissue adaptations in Celiac disease. This will involve shed cell transcriptomics and high-resolution spatial transcriptomics to thoroughly understand the turnover rates of various enterocyte sub-populations and tissue adaptations during the disease. Our innovative use of shed cell transcriptomics will add a dynamic dimension to human cell atlas reconstruction efforts, enriching our understanding of tissue processes in health and disease.