# The role of the mesenchymal niche in intestinal crypt fission

> **NIH NIH R03** · DANA-FARBER CANCER INST · 2024 · $125,700

## Abstract

Project Summary
Inflammatory bowel disorders and necrotizing enterocolitis represent insufficient epithelial repair,
stemming from failure of proper maintenance and expansion of resident intestinal stem cells (ISCs).
ISCs are housed in invaginations called crypts that expand during development and repair after
damage in a process called crypt fission. Little is understood of how crypt fission is mediated, however,
signaling factors including BMP inhibitors and non-canonical Wnts are implicated. ISCs are regulated
and maintained by similar signaling factors secreted by a surrounding mesenchymal environment called
“the niche”. It is unclear what role the niche plays in mediating crypt fission. The niche is composed of a
myriad of different cell types, including PDGFRA+ intestinal subepithelial myofibroblasts (ISEMFs) and
smooth muscle, that are anatomically, molecularly, and functionally distinct. ISEMFs occur closest to
the epithelial-mesenchymal barrier, express both BMPs and non-canonical Wnts; smooth muscle
populations occur beneath crypts and express abundant BMP inhibitors. Preliminary data suggests that
signaling from both ISEMFs and smooth muscle is required for proper crypt fission. Smooth muscle
ablation reduces crypt fission during development; however, functional co-culture assays show limited
smooth muscle support of organoid growth in vitro. ISEMFs, on the other hand, promote different
organoid co-culture phenotypes depending on level of BMP inhibitor added: in low levels, ISEMFs
promote differentiation, and in high levels, promote increased crypt budding, aka fission. My hypothesis
is that crypt fission is a process coordinated by the signaling activities of both ISEMFs and smooth
muscle. In Aim 1, I will investigate the anatomical and functional profiles of ISEMFs and smooth
muscle in crypt fission. I will determine when these cells occur during instances of crypt fission,
including postnatal development and repair after damage, test the requirement of ISEMFs in promoting
crypt fission in vivo, and sufficiency of ISEMFs and smooth muscle in directing crypt fission in vitro. In
Aim 2, I will test whether ISEMFs direct crypt fission via non-canonical Wnt signaling. Using both
in vitro and in vivo methods, I will determine the specific function of ISEMFs in directing crypt fission via
non-canonical Wnt5a. Together, these studies will provide fundamental insights into the collective
regulation of crypt fission via distinct mesenchymal niche populations during development and epithelial
repair, aiding our understanding of fundamental intestinal biology and disease.

## Key facts

- **NIH application ID:** 10783856
- **Project number:** 1R03DK138231-01
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Neil McCarthy
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $125,700
- **Award type:** 1
- **Project period:** 2024-03-01 → 2024-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783856

## Citation

> US National Institutes of Health, RePORTER application 10783856, The role of the mesenchymal niche in intestinal crypt fission (1R03DK138231-01). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10783856. Licensed CC0.

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