# Understanding stem cell heterogeneity and niche function in intestinal regeneration after irradiation

> **NIH NIH U01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $95,915

## Abstract

Project Summary
The radiation-induced gastrointestinal syndrome (RIGS) results from dose-dependent, cytocidal effects of
radiation on intestinal crypt cells. There are currently no approved medical countermeasures to alleviate the
RIGS. While active Lgr5+ stem cells are efficiently ablated, regeneration emerges from reserve, quiescent
progenitor/stem cells that are radio-resistant. The exact relationship between these two progenitor populations
(radio-resistant and radio-sensitive) remains undefined, and more information is needed to develop therapies
for RIGS and other disorders. An unbiased approach is critically needed to fully characterize the diversity of
cells in normal and regenerating intestine, independent of prior knowledge or purification assays. Work from
our lab and the ISCC has demonstrated a key role for the stromal mesenchyme and other niche cells in
modulating ISC homeostasis and regeneration, but a comprehensive regulatory model does not exist. Matrix
proteins are also part of the niche, and we have been able to grow both enteroids and human intestinal
organoids in tissue-specific hydrogels. Our investigators and collaborators have developed novel R-spondin
and Wnt agonists for in vivo delivery but the optimal combinations for treatment of RIGS have not been defined.
Thus, a full understanding of the cross-talk signals between ISCs and niche cells, and models for stimulating
or replacing intestinal ISCs, is needed for advances in therapy for RIGS. In collaboration with other members
of the ISCC, we are proposing two specific aims. Aim 1. How does the heterogeneity of intestinal crypt
cells and adjacent stromal cells change after radiation? We will analyze highly pure crypt epithelial cells
and stromal cells using a novel multiplex scRNA-seq platform before and after radiation, and apply
computational tools (metaVIPER) to develop a hierarchical structure and regulatory model. Aim 2. Can
therapy with niche factors or stem cells be used to mitigate radiation or inflammatory injury to the
intestine? We will study novel combinations of factors to mitigate RIGS, and then use tissue-specific hydrogels
and novel factors and cells to grow in vitro and transplant in vivo human intestinal organoids to treat colitis and
radiation proctitis. Overall, this proposal will use novel technology developed at Columbia/Einstein to advance
collaboratively the ISCC mission to regenerate the human intestine.

## Key facts

- **NIH application ID:** 10694315
- **Project number:** 3U01DK103155-09S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chandan Guha
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $95,915
- **Award type:** 3
- **Project period:** 2014-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694315

## Citation

> US National Institutes of Health, RePORTER application 10694315, Understanding stem cell heterogeneity and niche function in intestinal regeneration after irradiation (3U01DK103155-09S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10694315. Licensed CC0.

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