# Mechanisms of Hedgehog Regulation of Intestinal Villus Morphogenesis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $351,000

## Abstract

Abstract:
In the adult intestine, an organized array of finger-like projections called villi increase the surface area by 10-
fold to allow maximum absorptive function. Villi are covered by an endodermally-derived absorptive epithelial
layer, and contain a mesodermally-derived core of supporting tissues, including a tightly coupled vascular
network. Loss of villi by reduction in intestinal length or villus atrophy results in malabsorption resulting in death
in severe cases. Because villus development is primarily a fetal stage event, there are currently no therapeutic
strategies to increase absorptive surface area other than transplantation of donor intestine. Promising
advances have been made in engineering intestinal tissue using organoids, however these organoids fail to
form villi unless they are transplanted into a vascular rich environment of a host, such as the kidney capsule
(tHIO; transplanted human intestinal organoid), suggesting that vasculature may provide a key signal to
promote villus development. During fetal villus development, villus emergence (beginning at E14.5 from an
initially flat epithelium) requires Hedgehog (Hh) signaling for the formation of a patterned array of
mesenchymal clusters, which act as signaling centers. Clusters, which are composed mainly of PDGFRa+
cells, remain attached to the tips of emerging villi, becoming part of the villus core. New preliminary data
demonstrate that vascular tip cells interact with PDGFRa+ mesenchymal cells during cluster formation and that
perturbing vasculature with vasculature-specific small molecule inhibitors leads to a loss of cluster formation.
Furthermore, broadly inhibiting Hh signaling with small molecules perturbs the vasculature as well as the
clusters. Collectively, these data suggesting that endothelial cells play a central role in villus formation lead to
the following hypothesis: epithelial Hh ligands signal directly to endothelial cells to drive mesenchymal
cluster formation. This hypothesis will be tested and key gaps in knowledge addressed by 1) identifying the
Hh responsive cells within the cluster, 2) determining whether Hh signaling is necessary or sufficient within the
cluster cells and/or endothelial cells, 3) testing whether endothelial cells impact the generation of human
intestinal villi, and 4) defining the mechanisms that underlie the regulation of villus morphogenesis by Hh
signaling in the human intestine and human intestinal organoids. These studies, which exploit high resolution
microscopy, lineage tracing, genetic modulation of signaling and transcriptional profiling in both in vitro and in
vivo models of intestinal development, will expand our understanding of how villi are generated, reveal
new cell-cell interactions that control villus development and potentially lead to new therapeutic
strategies for villus growth in organoid systems.

## Key facts

- **NIH application ID:** 9869009
- **Project number:** 5R01DK121166-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Katherine Dempsey Walton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,000
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869009

## Citation

> US National Institutes of Health, RePORTER application 9869009, Mechanisms of Hedgehog Regulation of Intestinal Villus Morphogenesis (5R01DK121166-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9869009. Licensed CC0.

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