# Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease.

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $245,880

## Abstract

PROJECT SUMMARY
The overarching objective of our research is to develop a stem cell therapy from subcutaneous fat tissue
(SAT) to replace the congenitally absent enteric nervous system (ENS) in Hirschsprung disease (HSCR).
Surgical resection of the affected colon is currently the only viable treatment for HSCR. This is a necessary
life-saving procedure; albeit, more than 50% of patients still suffer from postoperative complications including
constipation, fecal incontinence, and enterocolitis. To overcome these morbidities, investigations into
treatments that can preserve the rectum and its functions are warranted. Replacement of the absent ENS via
stem cell therapies is touted as the most promising treatment strategy to achieve this goal. Our group has
demonstrated the feasibility of stem cell treatments by harvesting neural stem cells (NSCs) from the gut which
engraft, migrate and differentiate into neuronal networks when transplanted into mice with HSCR. For clinical
application this would require surgical resection of a piece of intestine. To prevent unnecessary resection
surgery, other sources of NSCs are of interest. Human fat (adipose) tissue contains a reservoir of stem cells
that are readily accessible. These cells have been examined in over 270 clinical trials for numerous diseases
that support favourable patient safety profiles. In our preliminary data we have also identified that nerve fiber
bundles from murine fat deposits – subcutaneous adipose tissue (SAT) - harbor an endogenous source of
NSCs that are unexplored for the treatment of neuropathies. We predict that the SAT could provide a useful
source of NSCs to treat colonic aganglionosis in HSCR; however, it remains undetermined if SAT-NSCs can
undergo neurogenesis in the aganglionic (absent ENS) environment of the gut and there are currently no
methods to purify and expand human SAT-NSCs. In the first aim of this study, we will determine if purified
SAT-NSCs from mice are capable of neurogenesis in aganglionic intestine. The ganglionated ENS is
supplemented postnatally by NSCs that migrate into the gut from extrinsic nerve fiber bundles and
differentiate into enteric neurons in response to environmental cues from the gut. We will address whether
SAT-NSCs can also undergo enteric neurogenesis when provided signalling cues from the ganglionic and
aganglionic gut in in vitro coculture systems and via microsurgical SAT-NSC implantation in vivo. To
determine how to isolate and expand human SAT-NSCs we will address the paucity of knowledge on the
origin of these cells. To accomplish this, cells isolated from human SAT nerve fiber bundles will be unbiasedly
characterised by single nuclei RNA-Seq before and after stem cell culture procedures. Cells expressing NSC
markers will be purified by fluorescence activated cell sorting and their differentiation potential will be
assessed in in vitro culture and in ex vivo transplants to the smooth muscle of the gut. The results of these
studies wi...

## Key facts

- **NIH application ID:** 10452149
- **Project number:** 1R21HD106036-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** ALLAN M GOLDSTEIN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $245,880
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452149

## Citation

> US National Institutes of Health, RePORTER application 10452149, Uncovering the therapeutic potential of adipose tissue derived neural stem cells for Hirschsprung's disease. (1R21HD106036-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10452149. Licensed CC0.

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