Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat.

Autor:	Furness JB; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Lei E; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia., Hunne B; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Adams CD; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia., Burns AJ; Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company International Inc., Boston, MA 02138, USA., Wykosky J; Gastroenterology Drug Discovery Unit, Takeda Pharmaceutical Company International Inc., Boston, MA 02138, USA., Fazio Coles TE; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Fothergill LJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Molero JC; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Pustovit RV; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia., Stamp LA; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3010, Australia.; Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria 3010, Australia.
Jazyk:	angličtina
Zdroj:	Disease models & mechanisms [Dis Model Mech] 2023 Jun 01; Vol. 16 (6). Date of Electronic Publication: 2023 Apr 27.
DOI:	10.1242/dmm.050055
Abstrakt:	Patients with Hirschsprung disease lack enteric ganglia in the distal colon and propulsion of colorectal content is substantially impaired. Proposed stem cell therapies to replace neurons require surgical bypass of the aganglionic bowel during re-colonization, but there is inadequate knowledge of the consequences of bypass. We performed bypass surgery in Ednrb-/- Hirschsprung rat pups. Surgically rescued rats failed to thrive, an outcome reversed by supplying electrolyte- and glucose-enriched drinking water. Histologically, the bypassed colon had normal structure, but grew substantially less in diameter than the functional region proximal to the bypass. Extrinsic sympathetic and spinal afferent neurons projected to their normal targets, including arteries and the circular muscle, in aganglionic regions. However, although axons of intrinsic excitatory and inhibitory neurons grew into the aganglionic region, their normally dense innervation of circular muscle was not restored. Large nerve trunks that contained tyrosine hydroxylase (TH)-, calcitonin gene-related peptide (CGRP, encoded by Calca or Calcb)-, neuronal nitric oxide synthase (nNOS or NOS1)-, vasoactive intestinal peptide (VIP)- and tachykinin (encoded by Tac1)-immunoreactive axons occurred in the distal aganglionic region. We conclude that the rescued Ednrb-/- rat provides a good model for the development of cell therapies for the treatment of Hirschsprung disease. Competing Interests: Competing interests A.J.B. and J.W. are employees of Takeda Pharmaceutical Company International Inc., and hold stock and/or stock options in Takeda. Other authors declare no competing or financial interests. (© 2023. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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