# Characterizing neurogenic progenitors in the adult intestine

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $356,230

## Abstract

Project Summary
The enteric nervous system (ENS) is of fundamental importance to human health through its regulation of all
aspects of gastrointestinal (GI) function, most notably gut motility. Congenital or acquired abnormalities of the
ENS consequently can lead to serious functional GI disorders, including esophageal achalasia, gastroparesis,
intestinal pseudo-obstruction, irritable bowel syndrome, Hirschsprung disease, and slow transit constipation.
The adult intestine is known to possess neuronal progenitors that can be utilized for regenerative cell therapy
to treat these neurointestinal diseases. However, to be able to stimulate endogenous enteric neurogenesis in
the adult intestine, or to improve current methods for culturing and expanding neuronal progenitors in a dish,
we need to understand the mechanisms that regulate the neurogenic response in the gut. In our current R01,
we have shown that a subset of enteric glial cells, highly enriched within the myenteric ganglia, possesses a
gene expression program and chromatin state predictive of neurogenic potential. These cells are capable of
undergoing rapid neuronal differentiation in response to specific stimuli, such as intestinal inflammation. The
overall objective of the current proposal is to define the cellular, molecular, and epigenetic signals that activate
this inflammatory-mediated neurogenic response in glia. Based on our preliminary studies, we propose the
following specific aims: (1) determine the role of muscularis macrophages and their inflammatory products in
promoting enteric neurogenesis; (2) investigate the role of Sox2 and Sox10 transcription factors in preventing
neuronal differentiation of enteric glia; and (3) characterize the phenotypic diversity and function of newly born
glial-derived neurons. This proposal is innovative in testing an immune-mediated mechanism for postnatal
enteric neurogenesis and does so utilizing state-of-the-art techniques, including CUT&RUN epigenomic
profiling, AAV-based gene silencing in vivo, neurosphere transplantation, and isolation and culture of
muscularis macrophages. The team provides expertise in ENS development, enteric neuronal stem cell
biology, ENS cell therapy, intestinal inflammation, bioinformatics, and clinical neurogastroenterology.
Successful completion of the proposed experiments will significantly enhance our understanding of the
mechanisms underlying neurogenesis in the adult intestine, identify new targets for pharmacotherapies that
can modulate enteric neurogenesis in vivo, and improve our ability to expand enteric neuronal progenitors in
vitro for cell therapy applications, including the development of cell transplantation for the treatment of
Hirschsprung disease and other neurointestinal diseases.

## Key facts

- **NIH application ID:** 10802625
- **Project number:** 2R01DK119210-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALLAN M GOLDSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $356,230
- **Award type:** 2
- **Project period:** 2020-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802625

## Citation

> US National Institutes of Health, RePORTER application 10802625, Characterizing neurogenic progenitors in the adult intestine (2R01DK119210-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10802625. Licensed CC0.

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