Biomedical Engineering Reference
In-Depth Information
The multilineage differentiation of NCSCs into glial and non-glial derivatives
in the developing nerve appears to be regulated by neuregulin, notch ligands,
and bone morphogenic proteins, as these factors are expressed in the develop-
ing nerve, and cause nerve NCSCs to generate Schwann cells and fibroblasts,
but not neurons, in culture. Nerve development is thus more complex than
was previously thought, involving NCSC self-renewal, lineage commitment,
and multilineage differentiation. Wild-type NCSCs engraft and form neurons
as efficiently in the aganglionic region of
Ednrb
-deficient gut as in wild-type
gut, demonstrating that the
Ednrb-
deficient hindgut is permissive for the sur-
vival and differentiation of neural progenitors (
33
) . This suggests a possible
new strategy for treating Hirschsprung disease, a birth defect that is some-
times caused by mutations in
Ednrb
and that is associated with a failure to
form enteric ganglia in the hindgut.
Ednrb
is required to modulate the response
of NCSCs to migratory cues; loss of
Ednrb
leads to a failure of these cells to
migrate into the hindgut, despite the fact that normal numbers of NCSCs are
maintained throughout development in the proximal gut (
34
) . The migration
defect can be bypassed by transplanting NCSCs into the aganglionic region of
the
Ednrb-
deficient embryonic gut. Transplanted alkaline phosphatase-
expressing neural crest cells (
34
) that have engrafted in the hindgut wall of an
Ednrb-
deficient rat have demonstrated the ability to gain new insights into the
etiology of disease as well as the ability to identify new potential therapeutic
approaches by studying the regulation of stem cell function. The identification
of NCSCs in the adult gut (enteric nervous system), with p75 (neurotrophin
receptor), has been done in a transverse section of the postnatal rat gut. NCSCs
were isolated from the adult gut by flow-cytometric purification of the cells
that expressed the highest levels of p75. In this section, the cells that stained
brightly for p75 localized to the myenteric and submucosal plexi of the enteric
nervous system (
34
). The profound impact of these data is in the fact that prior
to this work it was thought that NCSCs terminally differentiate during fetal
development and do not persist in the adult peripheral nervous system.
Glial cell-Derived Neurotrophic Factor (GDNF)
•
An understanding of the mechanisms that regulate organogenesis from stem
cells will make it possible to identify molecular links between stem cell func-
tion and disease (
32-
34
). Combined gene expression profiling with reverse
genetics and analyses of stem cell function in the hematopoietic and nervous
systems to identify mechanisms that regulate organogenesis from stem cells
and that lead to congenital disease when defective gave interesting results.
Hirschsprung disease is a relatively common birth defect characterized by a
failure to form enteric ganglia in the hindgut. It was found that it is caused by
mutations in two pathways (the GDNF and endothelin signaling pathways,
Ednrb pathway) that interact to regulate the generation and migration of NCSCs
in the gut (
32-
35
). Mutations in these pathways lead to a failure to form the
nervous system in the hindgut by preventing NCSCs from migrating into the
hindgut. These insights raise the possibility of treating this disease with stem
