# Epithelial stem cell dysfunction in diabetic oral ulcer

> **NIH NIH R03** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $158,500

## Abstract

PROJECT ABSTRACT
Diabetes mellitus significantly delays the healing of epidemic wounds as well as oral wounds, posing a difficult
clinical challenge for oral surgeries such as tooth extractions and free flaps. The lack of comprehensive
knowledge regarding the effects of diabetes on oral mucosal health hinders the design of effective treatment.
Our long-term goal is to identify novel therapeutic targets to improve diabetic wound management. In our
preliminary study, we discovered that long-lived Wnt-responsive cells are stem cells in oral epithelia. These cells
reside in the basal layer of the oral epithelium and maintain the tissue’s turnover and barrier function by precisely
balancing proliferation and differentiation. In response to injury, Wnt-responsive cells prioritize proliferation over
differentiation, producing abundant progeny to quickly re-epithelialize the wound. In diabetic mice, we recently
discovered that oral epithelia exhibit a decreased turnover rate and reduced structural protein expression. The
overall objective of this proposal is to determine how diabetes affects the quantity, distribution, activity, and injury
response of oral epithelial stem cells using both in vitro and in vivo models. Our central hypothesis is that diabetes
disrupts the microenvironment of oral epithelial stem cells, impairs stem cell fate, and thus adversely affects
epithelial barrier function and wound healing. Two independent but interconnected aims are proposed. In AIM 1,
we will determine the alterations that occur in oral epithelial stem cells and their niche under diabetic conditions.
Based on our preliminary data, we hypothesize that diabetes negatively impacts oral epithelial stem cells and
their niche, leading to slowed tissue turnover and compromised barrier function. A novel lineage-tracing strain
will be used to examine the quantity and activity of Wnt-responsive cells in an adult-onset type 2 diabetes model,
which closely resembles patient metabolic characteristics. Niche signaling will be interrogated by an in vitro 3D
coculture model. In AIM 2, we will define the key mechanisms responsible for delayed diabetic wound healing.
We hypothesize that the ineffective response of epithelial stem cells to injury is the primary cause of the
compromised healing of diabetic wounds. We will challenge control and diabetic mice with a traumatic oral ulcer
model and monitor the healing process, focusing on stem cell activation, proliferation, migration, and
differentiation. Results from this proposal will demonstrate for the first time the extent to which diabetes alters
epithelial stem cells in homeostasis and wound healing. These results are expected to have positive impacts, as
a comprehensive understanding of the compromised state of epithelial stem cells under diabetic conditions will
facilitate the development of effective therapies to enhance wound management.

## Key facts

- **NIH application ID:** 10886222
- **Project number:** 1R03DE033059-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Xue Yuan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $158,500
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10886222

## Citation

> US National Institutes of Health, RePORTER application 10886222, Epithelial stem cell dysfunction in diabetic oral ulcer (1R03DE033059-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10886222. Licensed CC0.

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