Intestinal epithelium: We have recently determined that excessive epithelial cell shedding from the villus tip in the human terminal ileum results in loss of intestinal barrier function, and surprisingly that this phenomenon is able to predict whether inflammatory bowel disease (IBD) is likely to relapse in the near future. Additionally, we have shown that epithelial cell specific gene regulation modulates their susceptibility to immune cell-derived inflammatory mediators. Further exploration of these interactions is necessary to develop both cellular and molecular therapeutics that will stimulate the rapid regeneration of the intestinal epithelium following intestinal barrier breakdown during active IBD. Our current research focuses on:
- Identifying key regulators of the intestinal stem cell niche, epithelial cell proliferation, differentiation and cell shedding in order to understand the processes that maintain intestinal barrier function and modulate an organism’s susceptibility to both intestinal and systemic diseases such as IBD and sepsis.
- Understanding the mechanisms of IBD pathogenesis in order to enable the development of novel therapies that target the rapid re-epithelialisation of the intestine to prevent bacterial invasion, inflammation and the breakdown of intestinal barrier function (features that are also present in Hirschsprung-associated enterocolitis).
- Generating 3D intestinal organoid co-culture models to determine signalling mechanisms between intestinal compartments. We aim to determine the bidirectional signalling mechanisms in co-cultures involving epithelial, immune, bacterial and ENS components in order to elucidate novel mechanisms to be targeted using regenerative medicine therapy approaches for IBD, Hirschsprung’s disease, short bowel syndrome and sepsis.
Key Investigators: Carrie Duckworth, Mark Pritchard, Barry Campbell
Cross-disciplinary collaborators: Janine Coombes, Chris Probert
Gastrointestinal researchers at Liverpool participate in the following major consortia: the FP7 Sysmed IBD research Programme.
To find out more, contact: Carrie Duckworth
Enteric nervous system: Hirschsprung's disease is a potentially life-threatening condition resulting from the congenital absence of ENS ganglion cells (aganglionosis) in the distal gut. We propose that transplantation of ENS progenitor cells into aganglionic bowel has the potential to provide a novel treatment for Hirschsprung’s disease. ENS progenitor cells can be isolated from the postnatal human gut and they proliferate in tissue culture as neurospheres, subsequently differentiating into neural cells by a Notch-dependent mechanism.
We have shown that transplanted neurosphere neurons can regulate gut contractility. We have recently made the surprising discovery that ENS progenitors can be derived from the glial cells of extrinsic (non-ENS) nerve fibres present in Hirschsprung’s aganglionic gut. This unexpected finding has prompted us to focus on issues like:
- Why do ENS progenitor cells not develop normally in Hirschsprung’s disease in vivo? We are following up new lines of research into the mechanisms involved in ENS development and the pathogenesis of Hirschsprung’s disease.
- ENS progenitor cells for autologous transplantation can be isolated from the patient’s own tissue normally discarded at surgery.
- The existence of progenitor cells in the aganglionic gut raises the novel possibility of inducing their differentiation in situ to treat Hirschprung’s disease.
Key Investigators: David Edgar, Simon Kenny, Bettina Wilm