Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improves Colon Structure and Function in Mouse Models of Hirschsprung Disease.

Gastroenterology
Rodolphe SoretNicolas Pilon

Abstract

Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR. We performed studies with four mouse models of HSCR: Holstein (HolTg/Tg, a model for trisomy 21-associated HSCR), TashT (TashTTg/Tg, a model for male-biased HSCR), Piebald-lethal (Ednrbs-l//s-l, a model for EDNRB mutation-associated HSCR), and Ret9/- (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to id...Continue Reading

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Citations

Jan 6, 2021·Cells·Verena Pawolski, Mirko H H Schmidt
Jan 15, 2021·Cellular and Molecular Gastroenterology and Hepatology·Christina M WrightRobert O Heuckeroth
Feb 9, 2021·Frontiers in Cell and Developmental Biology·Laura E KuilMaria M Alves
Dec 11, 2020·Scientific Reports·Armelle Tchoumi NereeMircea Alexandru Mateescu
Feb 26, 2021·Trends in Molecular Medicine·Nicolas Pilon
Mar 19, 2021·Nature Reviews. Gastroenterology & Hepatology·Luisa Seguella, Brian D Gulbransen
May 1, 2021·Journal of Immunology Research·José Rodrigues do Carmo NetoMarcos Vinícius da Silva
May 13, 2021·Nature Communications·Oraly Sanchez-FerrasMaxime Bouchard

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