Skin cells for healing intestinal wounds

Skin-like cells can heal colonic ulcers

The primary goal of treatments for inflammatory bowel disease is “mucosal healing,” which describes the complete healing of the intestines back to their healthy state. However, healing is not directly promoted by any of the available and limited medications. We have discovered that the body has an unusual but highly effective mode of intestinal healing that involves recruiting skin-like cells into wound. In this project, we are trying to understand how these under-appreciated skin-like cells can adapt to the intestine and ultimately restore organ function while providing long-term remission from disease.

How organ identity influences susceptibility to disease

Immune cell infiltration and crypt abscesses resulting from severe colitis

Why does inflammatory bowel disease primarily affect the intestines and not begin in some other organs? Why do mutations cause cancer in one organ but not another? The answers to these questions could guide effective treatments by asking what molecular mechanisms the “other” organs have that make them resistant to disease. In this project, we are studying how the unique pattern of cells in the intestines influences the inflammatory bowel disease-associated microbiome and the overall susceptibility to cancer. To perform these studies, we are replacing key elements of the intestinal architecture with cells of another organ.

Systems-level reconstruction of regenerative patterns during intestinal inflammation

Reconstructing the developmental trajectories of cells using machine learning

What causes the chronicity of autoimmune illnesses such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and others? We believe that these diseases involve the generation of abnormal stem cells; these stem cells produce a wide range of “daughter” cells that propagate these defects forward through many generations of cells. As a result, available treatments are not truly getting to the root cause of the disease at the stem-cell level. In this project, we are using next-generation techniques to identify and map the descendants of these disease-associated stem cells, in hopes of elucidating new therapeutic targets.

3D reconstruction of inflammatory bowel disease intestines for personalized medicine

3D imaging of the colon afflicted with inflammation

Current state-of-the-art techniques for examining intestinal tissue involve cutting the tissue into thin, 2-dimensional slices. While providing cellular resolution and relative ease of manipulation, these histological techniques largely obscure the 3-dimensional structure of the tissue. Unfortunately, the tissue remodeling that is seen in inflammatory bowel disease and colonic wound healing involves significant changes in 3D. We have developed an imaging technique for 3D-reconstruction of human intestinal tissue at cellular resolution; we are investigating whether this technique can yield new insights into the unique stem cell populations and cellular rearrangements that may define the disease state on a patient-by-patient level.