# Coordinated matricellular regulation of intestinal injury repair and regeneration

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $418,610

## Abstract

PROJECT SUMMARY
The intestinal epithelium, constantly challenged by environmental toxins, chemicals, or pathogens, is
continually being renewed and regenerated to maintain gut homeostasis through the proliferation and
differentiation of intestinal stem cells (ISCs). When this regenerative process is impaired, particularly in response
to injury, chronic inflammation and disease states such as inflammatory bowel disease may result. The
matricellular protein CCN1 has emerged as an overarching regulator of multiple functions in intestinal repair and
regeneration through its direct interactions with distinct integrin receptors in disparate cell types. Recently, we
have shown that CCN1 coordinately regulates ISC proliferation and differentiation into distinct epithelial cell types
through the regulation of Wnt and Notch signaling, in part by activating YAP, which contributes to epithelial
regeneration in homeostasis. In our new supporting data, we observed that (1) Mice with Ccn1 deletion in Lgr5+
ISCs and knock-in mice expressing integrins αv-binding defective CCN1 suffer high mortality and impaired
epithelial regeneration in dextran sulfate sodium (DSS)-induced injury. (2) Moreover, these knock-in mice fail to
restore the ISC pool after diphtheria toxin receptor-mediated ablation of the Lgr5+ ISCs, indicating that CCN1
may be required for the reprogramming or dedifferentiation of epithelial cells into ISCs. (3) Although senescent
cells are generally thought to be deleterious, mice treated with the senolytic drug ABT-263 to eliminate senescent
cells sustain impaired epithelial restitution after DSS injury, and similar defects are observed in knock-in mice in
which Ccn1 is unable to bind integrin α6β1 and are therefore unable to induce stromal fibroblast senescence.
These findings suggest that senescent fibroblasts promote intestinal epithelial repair and CCN1 may be a key
inducer of senescence. Based on these results, we will scrutinize the hypothesis that CCN1 is an overarching
regulator of intestinal injury repair by controlling both the dedifferentiation of epithelial cells to restore the ISC
pool and the induction of fibroblast senescence in the stroma through integrins αv and α6β1, respectively, with
the following specific aims: (Aim 1) To analyze how CCN1 regulates cell dedifferentiation to restore the ISC pool
upon injury and dissect the distinct functions of CCN1 and YAP in a regulatory loop to control this process. (Aim
2) To investigate the role of CCN1-induced stromal cell senescence in epithelial regeneration via the release of
the senescence regenerative factors (SRFs). These studies will yield new insights into a powerful endogenous
repair program that coordinately regulates complex cellular processes in various cell types for intestinal injury
repair and pave the way for novel targeted therapeutics that promote intestinal repair and regeneration following
injury.

## Key facts

- **NIH application ID:** 10773376
- **Project number:** 1R01DK137797-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Joon-Il Jun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,610
- **Award type:** 1
- **Project period:** 2024-03-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10773376

## Citation

> US National Institutes of Health, RePORTER application 10773376, Coordinated matricellular regulation of intestinal injury repair and regeneration (1R01DK137797-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10773376. Licensed CC0.

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