TITLE

REPLENISHMENT OF THE ENTERIC NERVOUS SYSTEM IN AGANGLIONOSIS

AUTHOR(S)
Thapar, N.; Bondurand, N.; Natarajan, D.; Pachnis, V.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA6
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
In humans aberrant development of the enteric nervous system (ENS) manifest as motility disorders. The commonest is Hirschsprung's disease. Mutations in a number of genes implicated in ENS development have been identified, eg receptor tyrosine kinase (RET), GDNF, Endothelin 3 (ET3), and Sox 10. Mouse models of aganglionosis share many of these mutations, providing good models for studying ENS development, isolation, and characterisation of ENS progenitor cells (EPCs), and their use to replenish aganglionic bowel. Myenteric plexus from wild type and mutant postnatal mouse guts were dissected out and cell cultures established. After culturing in defined medium large clusters of cells or neurosphere like bodies (NLBs) were isolated. Dissociated NLBs were infected with a retroviral vector containing a fluorescent protein incorporated into dividing cells. Positive cells were selected using a FACS cell sorter and characterised for the properties of stem cells. The effects of various growth factors, eg ET3 and GDNF, were studied. Labelled cells were injected into wild type and mutant gut in organ culture to assess their ability to migrate co onise the gut and differentiate into mature ENS cell types. Cultures of cells isolated from postnatal wild type and mutant gut gave rise to NLBs with 30% of sorted cells exhibiting EPC characteristics. At clonal density single cells gave rise to both neurons and glia. In sub-clonol studies such colonies when re-plated at clonal density showed self-renewal and multi-potency. Preliminary results suggest that ET3 and GDNF alter EPC differentiation and proliferation. Injected cells migrate, proliferate, and differentiate into neurons and glia. This is one of the first descriptions and isolation of EPCs from postnatal gut. They have the properties of stem cells and appear to be modulated by ET3 and GDNF. Injection experiments to date are encouraging as a degree of replenishment is observed. We describe for the first time isolation of...
ACCESSION #
9747289

 

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