Isolation of enteric nervous system progenitor cells from the aganglionic gut of patients with Hirschsprung's disease
Isolation of enteric nervous system progenitor cells from the aganglionic gut of patients with Hirschsprung's disease
Enteric nervous system progenitor cells isolated from postnatal human gut and cultured as neurospheres can then be transplanted into aganglionic gut to restore normal patterns of contractility. These progenitor cells may be of future use to treat patients with Hirschprung's disease, a congenital condition characterized by hindgut dysmotility due to the lack of enteric nervous system ganglia. Here we demonstrate that progenitor cells can also be isolated from aganglionic gut removed during corrective surgery for Hirschsprung's disease. Although the enteric nervous system marker calretinin is not expressed in the aganglionic gut region, de novo expression is initiated in cultured neurosphere cells isolated from aganglionic Hirschsprung bowel. Furthermore, expression of the neural markers NOS, VIP and GFAP also increased during culture of aganglionic gut neurospheres which we show can be transplantation into cultured embryonic mouse gut explants to restore a normal frequency of contractility. To determine the origin of the progenitor cells in aganglionic region, we used fluorescence-activated cell sorting to demonstrate that only p75-positive neural crest-derived cells present in the thickened nerve trunks characteristic of the aganglionic region of Hirschsprung gut gave rise to neurons in culture. The derivation of enteric nervous system progenitors in the aganglionic gut region of Hirschprung's patients not only means that this tissue is a potential source of cells for future autologous transplantation, but it also raises the possibility of inducing the differentiation of these endogenous cells in situ to compensate for the aganglionosis.
Wilkinson, David J.
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Bethell, George S.
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Shukla, Rajeev
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Kenny, Simon E.
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Edgar, David H.
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18 May 2015
Wilkinson, David J.
13ef61ab-5c37-4359-b06e-11c72e4e416d
Bethell, George S.
c7a62cc1-5573-41f6-ae00-3c11e8219dd4
Shukla, Rajeev
8c2fdd02-9fe1-42c3-96e1-2be5bda1e138
Kenny, Simon E.
9e0d8c3f-44d3-45db-9329-c70650d7d67e
Edgar, David H.
44d2ebae-8777-45b4-9f2d-c6f72fa638b8
Wilkinson, David J., Bethell, George S., Shukla, Rajeev, Kenny, Simon E. and Edgar, David H.
(2015)
Isolation of enteric nervous system progenitor cells from the aganglionic gut of patients with Hirschsprung's disease.
PLoS ONE, 10 (5), [e0125724].
(doi:10.1371/journal.pone.0125724).
Abstract
Enteric nervous system progenitor cells isolated from postnatal human gut and cultured as neurospheres can then be transplanted into aganglionic gut to restore normal patterns of contractility. These progenitor cells may be of future use to treat patients with Hirschprung's disease, a congenital condition characterized by hindgut dysmotility due to the lack of enteric nervous system ganglia. Here we demonstrate that progenitor cells can also be isolated from aganglionic gut removed during corrective surgery for Hirschsprung's disease. Although the enteric nervous system marker calretinin is not expressed in the aganglionic gut region, de novo expression is initiated in cultured neurosphere cells isolated from aganglionic Hirschsprung bowel. Furthermore, expression of the neural markers NOS, VIP and GFAP also increased during culture of aganglionic gut neurospheres which we show can be transplantation into cultured embryonic mouse gut explants to restore a normal frequency of contractility. To determine the origin of the progenitor cells in aganglionic region, we used fluorescence-activated cell sorting to demonstrate that only p75-positive neural crest-derived cells present in the thickened nerve trunks characteristic of the aganglionic region of Hirschsprung gut gave rise to neurons in culture. The derivation of enteric nervous system progenitors in the aganglionic gut region of Hirschprung's patients not only means that this tissue is a potential source of cells for future autologous transplantation, but it also raises the possibility of inducing the differentiation of these endogenous cells in situ to compensate for the aganglionosis.
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Published date: 18 May 2015
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Funding Information:
We acknowledge the expert technical assistance of Angelica Mesa. We would like to thank the children and families who consented to participate in this study, together the support from the CHAMPS (Curing Hirschsprung's and Making Positive Steps) Appeal.
Publisher Copyright:
© 2015 Wilkinson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Local EPrints ID: 483497
URI: http://eprints.soton.ac.uk/id/eprint/483497
ISSN: 1932-6203
PURE UUID: eb506a4c-afb4-47f1-bf22-2e86dd5aad05
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Date deposited: 31 Oct 2023 18:24
Last modified: 06 Jun 2024 02:15
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Contributors
Author:
David J. Wilkinson
Author:
George S. Bethell
Author:
Rajeev Shukla
Author:
Simon E. Kenny
Author:
David H. Edgar
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