# How Patterned Mesenchymal-Epithelial interactions Shape Intestinal Crypts

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $596,962

## Abstract

Project Summary/Abstract
The colonic epithelium is the site of a host of human diseases, and therefore understanding its development and
function is essential for human health. The colon epithelium is separated into morphologically and functionally
distinct domains, with proliferative stem cells being housed at the bottom of the crypts of Lieberkühn, whereas
differentiated cells populate the epithelium closest to the lumen. The maintenance of epithelial homeostasis in
the crypt is dictated in large part by spatially patterned signals from the underlying mesenchyme. The
mesenchymal cells involved in adult colonic crypt homeostasis have been of recent interest. However, little is
known about the molecular mechanisms underlying colonic crypt formation during development. Our proposal
will determine how mesenchymal cell populations and signals interact with the developing epithelium to
drive colonic crypt morphogenesis and define stem cell dynamics during development and regeneration.
We will accomplish this work through our three aims: First, we will map mesenchymal-epithelial interactions over
the course of colonic crypt development using single cell RNAseq and histological approaches. We will then use
genetically modified mouse models to investigate the specific role of mesenchymal WNT signals in three stages
of colonic crypt development: invagination, elongation, and fission of colonic crypts. Second, we will investigate
the potential re-activation of an embryonic program in both the epithelium and mesenchyme following injury
induced by DSS treatment. We will test the ability of embryonic or injury-associated mesenchyme to stimulate
plasticity, defined as de-differentiation of committed progenitors to a more multipotent state, in the adult
epithelium. Third, we will take a synthetic approach to reconstruct patterned mesenchymal signals around colon
spheroids, and we will use this new model to test the sufficiency of polarized WNT signals to drive colonic crypt
formation in vitro. Overall, our project leverages a combination of in vivo studies, in vitro models, synthetic
engineering and bioinformatic approaches. This comprehensive scope is made possible through a highly
collaborative environment at UCSF and the productive partnership of the two principal investigators carrying out
this project. The findings from this proposal will significantly advance our basic knowledge of colon development
and regeneration, highlighting the dynamics of mesenchymal-epithelial crosstalk. This will have implications
beyond our fundamental understanding of colon biology and will help pave the way for discovery of therapeutic
strategies to treat and modulate colonic disease.

## Key facts

- **NIH application ID:** 10338737
- **Project number:** 1R01DK130969-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ophir D Klein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $596,962
- **Award type:** 1
- **Project period:** 2022-02-15 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10338737

## Citation

> US National Institutes of Health, RePORTER application 10338737, How Patterned Mesenchymal-Epithelial interactions Shape Intestinal Crypts (1R01DK130969-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10338737. Licensed CC0.

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