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Nikhil Thapar and Conor McCann's Research Group


Enteric nervous system development and repair group

Neurospheres containing enteric nervous system stem cells

Dr Thapar and Dr McCann lead a research programme studying the pathogenesis of gut motility disorders. We have a particular focus on their underlying molecular and genetic mechanisms, improving their diagnosis, and developing novel approaches, including stem cells and gut tissue engineering, for their treatment.

Normal gastrointestinal (GI) contraction and function requires the coordinated interaction of the enteric neurons and glial cells that comprise the enteric nervous system (ENS), interstitial cells of Cajal, and smooth muscle cells.

Defects in the development of these cell types results in a range of commonly occurring gut disorders/diseases including Hirschsprung disease (aganglionic megacolon), intestinal pseudo-obstruction, and other motility defects. We are particularly interested in the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract. The ENS is entirely derived from neural crest cells (NCC) and these precursors undergo extensive migration, proliferation and differentiation in order to colonise the entire length of the gut and form the ENS.

Defects in these processes can result in the congenital disorder Hirschsprung disease (HSCR), where variable lengths of the hindgut remain aganglionic, resulting in tonic contraction of the aganglionic colon segment and functional obstruction.  Understanding the underlying molecular and cellular pathogenesis of this and other neuromuscular diseases of the gastrointestinal tract drives our research.

Chick hindgut being colonised by GFP-expressing neural crest cells

Enteric neurons (green) located between smooth muscle cells (red) of the gut wall
Chick hindgut being colonised by GFP-expressing neural crest cellsEnteric neurons (green) located between smooth muscle cells (red) of the gut wall

We take a number of approaches, in collaboration with groups locally, nationally and internationally to:

  • Investigate the mechanisms underlying enteric nervous system (ENS) development from neural crest derived precursors
  • Determine, by functional analysis, whether candidate genes identified in enteric neuropathies and myopathies, are actually disease causing genes
  • Better understand the underlying pathophysiology of enteric neuropathies
  • Develop novel stem cell-based therapies for aganglionic gut disorders such as Hirschsprung disease
  • Use tissue engineering approaches to manufacture replacements for diseased gut
Projects
Key Publications

Cooper et al (2016) In vivo transplantation of fetal human gut-derived enteric neural crest cells. Neurogastroenterology and Motility (Epub ahead of print). (PDF)

Burns et al (2016) White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Developmental Biology 417(2): 229-51. (PDF)

Cooper et al (2016) In Vivo Transplantation of Enteric Neural Crest Cells into Mouse Gut; Engraftment, Functional Integration and Long-Term Safety. PLOS ONE 11(1):e0147989. (PDF)

Burns, A.J., Thapar, N. (2014). Stem cell therapies for gut neuromuscular disorders. Nature Reviews Gastroenterology and Hepatology 11; 317-328. (PDF)

Wang et al (2011) Analysis of the sacral neural crest cell contribution to the hindgut enteric nervous system in the mouse embryo. Gastroenterology 141(3): 992-1002. (PDF)

Metzger et al (2009) Enteric nervous system stem cells derived from human gut mucosa for the treatment of aganglionic gut disorders. Gastroenterology 136 (7), 2214-2225. (PDF)

Barlow et al (2008) Critical numbers of neural crest cells are required in the pathways from the neural tube to the foregut to ensure complete enteric nervous system formation. Development 135(9), 1681-91. (PDF)

 

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