# Regulation of the Intestinal Stem Cells During Regeneration

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $474,521

## Abstract

Intestinal stem cells (ISCs) mediate the regenerative response that follows injury to the gut,
though the mechanisms that regulate these essential cells remain poorly understood. In the
adult, Wnt-responsive Wnt(+) Lgr5+ ISCs are required for intestinal maintenance, but these cells
are exquisitely sensitive to injury (e.g., irradiation, inflammation, fasting). In contrast, a reserve
population of dormant (d)-ISCs, such as those marked by mTert expression, are highly resistant
to injury and become activated to restore Lgr5+ ISCs and tissue homeostasis. Our recent data
indicate that d-ISCs (unlike Lgr5+ cells) are maintained in a Wnt-unresponsive Wnt(-) state.
Similarly, fetal ISCs are Wnt(-) before birth and mature into Wnt(+) ISCs during the perinatal
transition from intra- to extra-uterine life in response to unknown factors. Together, these
observations suggest that the transition from a Wnt(-) to a Wnt(+) state is a crucial process for
the generation of Lgr5+ ISCs during regeneration and development. Our recent analyses, using
RNA-seq to compare Wnt(-) and Wnt(+) ISC populations, revealed multiple differentially
expressed genes, underscoring that distinct regulatory pathways control these two ISC
populations. Precisely how the Wnt(-) state is maintained in d-ISCs and how it impacts their
regenerative response is largely unknown. To address this, we propose the following:
Aim 1. Define the role of candidate regulatory factors and the identity of long-lived d-ISCs;
Aim 2. Determine how the microbiome and/or its metabolites regulate ISC survival; and
Aim 3. Investigate the role of human (h)Tert+ cells in intestinal homeostasis.
These studies seek to understand the regulatory mechanisms that govern Wnt(-) ISC
maintenance and survival and regulate their transition into Wnt(+) ISCs. The successful
completion of these studies may lead to targeted new regenerative therapies for patients
suffering from inflammatory bowel disease, short gut syndrome, environmental enteropathy and
intestinal toxicity resulting from exposure to radiation and chemotherapy.

## Key facts

- **NIH application ID:** 10197117
- **Project number:** 5R01DK119488-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** David T Breault
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $474,521
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197117

## Citation

> US National Institutes of Health, RePORTER application 10197117, Regulation of the Intestinal Stem Cells During Regeneration (5R01DK119488-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197117. Licensed CC0.

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