# Pathogenic Heterogeneity in Mucosal Stem Cells in Pediatric Crohn's Disease

> **NIH NIH R01** · UNIVERSITY OF HOUSTON · 2021 · $640,193

## Abstract

DESCRIPTION
Crohn's disease is a remarkably prevalent and aggressive form of inflammatory bowel disease that often
progresses to strictures, fistulas, and perforations requiring surgical intervention. Powerful
immunosuppression and anti-inflammatory therapies have not altered the reliance on surgery, fueling the
search for therapies that target the etiology of this condition. Major advances in genetics and pathophysiology
in the past decade have now clearly established that Crohn's, and inflammatory bowel diseases in general, are
pathologies in the management of gut microbes by the immediate epithelial lining and cells of the innate and
adaptive immune system. Support for this notion comes from recent genome-wide association studies (GWAS)
that, in addition to the expected immune regulatory genes, have implicated a vast network of genes linked to
the intestinal epithelia. A major gap in our understanding the role of intestinal epithelia in Crohn's and other
inflammatory bowel diseases has been the lack of robust in vitro cultivation systems to test epithelial function
separate from confounding influences of the inflamed gut. We have now developed reliable technologies to
clone so-called “ground state” stem cells from each region of the human gastrointestinal tract and have shown
them to possess epigenetic memory of and capacity for precise 3-D differentiation consistent with their origins
despite months of continuous cultivation. This same technology now has been used to capture stem cells from
endoscopic biopsies of Crohn's patients. Unexpectedly, biopsies from these patients yield two distinct
populations of epithelial stem cells including one identical to those of control patients and another marked by a
stable inflammatory gene signature and profound defects in the differentiation of secretory cell types.
Significantly, we now have strong preliminary evidence that these two properties of the aberrant stem cells are
the result of a profound epigenetic transformation of cells of the terminal ileum to those of proximal intestine.
In three specific aims, we will test hypotheses that 1) this population of aberrant stem cells confers a mucosal
hypersensitivity to microbial products, 2) that the combination of secreted chemokines and cytokines produced
by these aberrant stem cells is sufficient to promote an inflammatory state in the mucosa, and 3), that the
aberrant stem cells we identified in Crohn's represent a permanent and epigenetically enforced switch from a
terminal ileum to a proximal intestine state and along with that switch both the hypersensitivity and
proinflammatory phenotypes. We anticipate that these studies will provide novel insights into the cell biology of
Crohn's, the role of mucosal stem cell heterogeneity in the pathological interactions between the immune
system, the microbiome, and the intervening intestinal mucosa, and provide insights into potential therapeutic
targets for the mitigation of this and inflammatory bowel dis...

## Key facts

- **NIH application ID:** 10202569
- **Project number:** 5R01DK115445-05
- **Recipient organization:** UNIVERSITY OF HOUSTON
- **Principal Investigator:** Wa Xian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $640,193
- **Award type:** 5
- **Project period:** 2018-08-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10202569

## Citation

> US National Institutes of Health, RePORTER application 10202569, Pathogenic Heterogeneity in Mucosal Stem Cells in Pediatric Crohn's Disease (5R01DK115445-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10202569. Licensed CC0.

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