# Development and vascularity of intestinal mesenchyme

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2024 · $430,180

## Abstract

Project Summary
 Adult digestive epithelia depend on adjacent mesenchyme to sustain intestinal stem cells (ISCs) at the
crypt base and drive cell maturation at the villus base. Precisely layered cells that provide redundant and
partially overlapping “trophic” factors execute these essential polarized functions. Our lab’s contributions to
this emerging understanding include deep characterization of small intestine (SI) and colonic mesenchyme,
discovery of potent “trophocytes,” a cellular explanation for the crypt BMP signaling gradient, identification
of the authentic source of canonical Wnt ligands, and discovery of niche self-organization. Importantly,
work from several groups converges on nearly identical consensus cell populations in mouse and human
intestines. Strategically localized fractions of the most abundant cells (which express low PDGFRA),
including distinct CD81+ trophocytes, represent notable functional niche elements. In the developing gut
mesoderm, PDGFRAlo cells seem to give rise to key structural elements, such as different smooth muscle
(SM) compartments and unique intestinal capillaries, before the remaining PDGFRAlo cells generate the
ISC niche. Against the backdrop of a complete census of adult mesenchymal cells, these findings pave the
way to understand their embryonic origins in modern mechanistic terms. This simple but crucial tissue thus
offers opportunities to address a broad, fundamental question in developmental biology: How does an
embryonic anlage with limited external cell input achieve and retain its adult form? Because injured
intestines must reconstitute the mesenchymal compartment, the answers have important implications for
understanding and treating ulcerative and other forms of intestinal damage. Prior investigation of signaling
in intestinal development elegantly implicates Hedgehog (Hh, from endoderm) and BMP (from mesoderm)
in specifying at least SM and endothelial cells (EC), and possibly other compartments, but how these
signals elicit distinct cell fates in ostensibly similar progenitors remains unclear. Discrete cell identities
reflect opening and closing of thousands of different cis-regulatory elements (CREs); to deconstruct steps
that lie between a mesodermal anlage and the functional tissue into which it develops, we propose to study
the chromatin basis of SM (Aim 1) and EC (Aim 2) differentiation. We will map mesenchymal ontogeny
rigorously with respect to signature CREs for each resident cell type (Aims 1A and 1B), then investigate in
primary fetal cell cultures how Hh activity and BMP inhibition together induce the CRE complement
necessary for naïve precursors to undergo SM differentiation (Aim 1C). We then ask how the same signals
(albeit likely in different forms or concentrations) induce ECs in similar progenitors (Aim 2A). Finally, we
propose studies for mechanistic insight into processes designed for intestinal capillary growth to match, but
not exceed, resting tissue demands (Aim 2B). Tog...

## Key facts

- **NIH application ID:** 10867407
- **Project number:** 5R01DK121540-06
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Ramesh A Shivdasani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $430,180
- **Award type:** 5
- **Project period:** 2019-06-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867407

## Citation

> US National Institutes of Health, RePORTER application 10867407, Development and vascularity of intestinal mesenchyme (5R01DK121540-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10867407. Licensed CC0.

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