title: Presence of intramucosal neuroglial cells in normal and aganglionic human colon.
abstract: The enteric nervous system (ENS) is composed of neural crest-derived neurons (also known as ganglion cells) the cell bodies of which are located in the submucosal and myenteric plexuses of the intestinal wall. Intramucosal ganglion cells are known to exist but are rare and often considered ectopic. Also derived from the neural crest are enteric glial cells that populate the ganglia and the associated nerves, as well as the lamina propria of the intestinal mucosa. In Hirschsprung disease (HSCR), ganglion cells are absent from the distal gut because of a failure of neural crest-derived progenitor cells to complete their rostrocaudal migration during embryogenesis. The fate of intramucosal glial cells in human HSCR is essentially unknown. We demonstrate a network of intramucosal cells that exhibit dendritic morphology typical of neurons and glial cells. These dendritic cells are present throughout the human gut and express Tuj1, S100, glial fibrillary acidic protein, CD56, synaptophysin, and calretinin, consistent with mixed or overlapping neuroglial differentiation. The cells are present in aganglionic colon from patients with HSCR, but with an altered immunophenotype. Coexpression of Tuj1 and HNK1 in this cell population supports a neural crest origin. These findings extend and challenge the current understanding of ENS microanatomy and suggest the existence of an intramucosal population of neural crest-derived cells, present in HSCR, with overlapping immunophenotype of neurons and glia. Intramucosal neuroglial cells have not been previously recognized, and their presence in HSCR poses new questions about ENS development and the pathobiology of HSCR that merit further investigation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Nemours Children's Hospital, Orlando, Florida;
authors.forename: Kamran
authors.initials: K
authors.lastname: Badizadegan
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Alyssa R
authors.initials: AR
authors.lastname: Thomas
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Human Morphology and Developmental Biology, Faculty of Medicine, Semmelweis University, Budapest, Hungary; and.
authors.forename: Nandor
authors.initials: N
authors.lastname: Nagy
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Dorothy
authors.initials: D
authors.lastname: Ndishabandi
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Miller
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
authors.forename: Alessandro
authors.initials: A
authors.lastname: Alessandrini
authors.affiliation: Division of Pediatric Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jaime
authors.initials: J
authors.lastname: Belkind-Gerson
authors.affiliation: Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; agoldstein@partners.org.
authors.forename: Allan M
authors.initials: AM
authors.lastname: Goldstein
mesh_terms: D015415:Biomarkers / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D018959:CD57 Antigens / Q000032:analysis; D064032:Calbindin 2 / Q000032:analysis; D016022:Case-Control Studies; D002454:Cell Differentiation; D019070:Cell Lineage; D048430:Cell Shape; D003106:Colon / Q000737:chemistry / Q000473:pathology*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006627:Hirschsprung Disease / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007413:Intestinal Mucosa / Q000737:chemistry / Q000473:pathology*; D009457:Neuroglia / Q000737:chemistry / Q000473:pathology*; D009418:S100 Proteins / Q000032:analysis; D016708:Synaptophysin / Q000032:analysis; D014404:Tubulin / Q000032:analysis
chemical_list: D015415:Biomarkers; C576764:CALB2 protein, human; D019002:CD56 Antigen; D018959:CD57 Antigens; D064032:Calbindin 2; D005904:Glial Fibrillary Acidic Protein; C522918:NCAM1 protein, human; D009418:S100 Proteins; C569014:SYP protein, human; D016708:Synaptophysin; C498585:TUBB3 protein, human; D014404:Tubulin
keywords: Hirschsprung disease; enteric glial cells; enteric nervous system