# Regulation of Niche Cell Differentiation to Sustain Intestinal Stem Cell Regeneration Against Gut Inflammation

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $357,750

## Abstract

Project Summary: Intestinal Clostridium difficile infection (CDI) has increased in patients with inflammatory
bowel disease (IBD) over the past decade, resulting in a major healthcare burden. Therapeutic approaches for
this comorbidity are extremely limited, however, due to the current lack of understanding of the essential cell
types and key signaling proteins involved in CDI that exacerbate IBD. It is believed that along with niche cells,
Lgr5hi and Lgr5low intestinal epithelial stem cells (IESCs) control intestinal epithelial (IEC) lineage repair
following acute mucosal injuries. Further, the formation of intestinal Paneth cell (PC) or colonic deep crypt
secretory cell (DCS) niche cells are differentially regulated by opposing Wnt and Notch signaling. Inducing
IESCs to give rise to these niche cells could mitigate CDI in the setting of IBD or promote IESC repair of IECs
in IBD. However, how IESCs are sustained to specify PCs and DSCs that in turn sustain IESC regeneration
remains unclear. We reported that the activation of Tyrosine phosphorylated (pYSTAT5) promoted IESC
regeneration following acute ileitis and colitis. Importantly, single nucleotide polymorphisms (SNPs) in JAK2 or
STAT5A have been linked to IEC healing defects, CDI, and IBD complications. JAK2 SNP carriage is
associated with two-fold higher rates of CDI in pediatric Crohn’s disease with synchronous ileal-colonic location
(ileocolitis). However, whether JAK2 or STAT5A SNPs in IBD are critical to determine the susceptibility to
comorbid CDI is not known. Our current data show that a single STAT5A SNP reduces stem cell survival. Stat5
depletion leads to a severe pseudomembranous colitis compared to controls; in contrast, constitutively active
STAT5A (Ca-pYSTAT5) reactivates Lgr5low IESCs toward PCs and increases production of secreted niche
factors. Therefore, we hypothesize that Ca-pYSTAT5 regulates IESCs to give rise to PC and DCS niche cells
that in turn sustain IESC regeneration and that the SNPs in the JAK2-STAT5 pathway impair Ca-pYSTAT5,
leading to IBD with comorbid CDI. We will test this hypothesis by addressing the following Specific Aims. In
Aim 1, we will examine the effects of genetic defects in JAK2-STAT5 on IBD and CDI comorbidity rates, IESC
regeneration, and niche cell differentiation. We will test the effects of JAK2 or STAT5A SNP on de novo IESC
niche cell differentiation. These studies will determine why CDI frequently occurs in IBD and will suggest a
potential therapeutic target to reduce the prevalence of CDI with IBD. In Aim 2, we will define the mechanisms
by which Ca-pYSTAT5 regulates IESC niche cell differentiation. We will determine the effects of reduced Stat5
expression, pYSTAT5 level and knock-in of the STAT5A SNP in mice on the susceptibility of colitis to CDI.
These studies will test the link between defective JAK2-pYSTAT5 and IBD comorbid with CDI. Collectively, our
proposal will identify an intestinal lineage-restricted transcription factor for IE...

## Key facts

- **NIH application ID:** 9864582
- **Project number:** 1R01DK123299-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Xiaonan Han
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,750
- **Award type:** 1
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864582

## Citation

> US National Institutes of Health, RePORTER application 9864582, Regulation of Niche Cell Differentiation to Sustain Intestinal Stem Cell Regeneration Against Gut Inflammation (1R01DK123299-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9864582. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*