MRC National Institute for Medical Research, London
Science for Health
Neurogenic potential of glial cells in the gut of adult animals
25 August 2011
Scientists at NIMR have discovered that glial cells within the gut of adult animals are capable of generating enteric neurons in response to injury. The research is published in the Journal of Clinical Investigation.
The nervous system of the gastrointestinal tract regulates motility and secretions of the gut wall and has a crucial role in digestive function. The enteric nervous system (ENS) is derived from a relatively small number of neural crest cell progenitors which originate during embryogenesis in the brain and after extensive proliferation and migration colonize the entire length of the gastrointestinal tract. The vast majority of enteric neurons in adult animals are generated during embryonic and early postnatal life, and in contrast to the brain, neurogenesis is undetectable in the nervous system of the gut under steady state conditions. Nevertheless, neurogenic progenitors have been identified readily in cultures of adult ENS and new enteric neurons can be generated in the gut of adult mice in response to pharmacological stimulation. The identity of these progenitors and their relationship to embryonic ENS precursors however remained unclear.
Catia Laranjeira, in the laboratory of Vassilis Pachnis (pictured) lab in NIMR's Division of Molecular Neurobiology, and Alexandre Potocnik, from the Division of Molecular Immunology, have combined genetic fate mapping, cultures of dissociated enteric ganglia and an ENS injury model in mice to prospectively identify ENS progenitors and follow their developmental potential in vivo. They have demonstrated that neural crest cells marked by SRY box-containing gene 10 (Sox10) generate in vivo the neurons and glia cells of enteric ganglia. The contribution of Sox10-marked progenitors to the adult pool of enteric neurons is temporally regulated. Enteric neurogenesis is at the highest during midgestation but afterwards is reduced and eventually ceases between 1 and 3 months of postnatal life. Remarkably, Sox10-expressing glia cells from the myenteric plexus of adult mice are capable of generating in culture neurons with morphological, molecular and functional characteristics of intrinsic enteric neurons. The neurogenic potential of enteric glia can also be activated in vivo in response to chemical injury to the enteric ganglia. These results indicate that despite the absence of constitutive neurogenesis in the adult gut, enteric glia maintain neurogenic potential which can be activated by tissue dissociation or injury.
Degeneration of enteric neurons is a common feature of gut inflammation and Parkinson's disease. The ability of enteric glia in adult animals to generate enteric neurons could have therapeutic implications for the treatment of severe inflammatory conditions and digestive syndrome associated with common neurodegenerative conditions. In addition, understanding the mechanisms that regulate the neurogenic potential of enteric glia could facilitate the design of novel therapeutic strategies for the treatment of conditions associated with congenital absence of enteric neurons, such as Hirschsprung's disease.
Our data provide a framework for exploring the molecular mechanisms that control enteric neurogenesis and identify glial cells as a potential target for cell replacement therapies in diseases associated with congenital absence or acquired loss of enteric neurons.
Vassilis Pachnis
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Confocal microscope image of a myenteric ganglion from tamoxifen and BAC-treated SER26 mice immunostained for YFP (green), the pan-neuronal marker HuC/D (red) and the glial marker S100â (blue) three months after treatment. In these transgenic mice tamoxifen administration activates YFP in glial cells and BAC treatment induces a localised injury to the myenteric plexus. Yellow cells express the lineage reporter YFP and the neuronal marker HuC/D indicating that they are derived from enteric glial cells.
Neurogenic potential of glial cells in the murine enteric nervous system
Catia Laranjeira, Katarina Sandgren, Nicoletta Kessaris, William Richardson, Alexandre Potocnik, Pieter Vanden Berghe and Vassilis Pachnis (2011)
Journal of Clinical Investigation Epub ahead of print. Fulltext.
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