Defects in long-distance neuronal wiring in the large intestine and in Hirschsprung’s disease

The details

Project aims:

• To understand the enteric nervous system circuitry in the mouse ileo-colonic junction and mid-distal colon transition.
• To use mouse precursors and iPSC technology for targeted repair of subtle or more severe defects in ENS wiring.
• Investigate whether Hirschsprung’s disease tissue is permissive to (iPSC) induced progenitor implantation.

The gastrointestinal (GI) tract is a complex organ that plays essential roles in the propulsion of food and waste products, nutrient and energy uptake, as well as host defence. The enteric nervous system (ENS), a meshed network of neurons and glia, controls most of these functions.

During development, progenitor cells migrate down the gut and colonize the entire intestinal tube to form the ENS. However, in 1 out of 5000 live births, these progenitors do not reach the terminal end, causing the debilitating Hirschsprung’s disease, a condition in which innervation is absent from short or longer segments of the large intestine.

The underlying reasons are still largely unknown. Apart from this severe disorder, also subtler ENS defects can cause gut malfunction and discomfort. This is not surprising, as progenitors have the daunting task to travel long distances and bridge important junctions (oesophagus to stomach, pylorus to the duodenum or distal ileum to colon).

In this project, we will investigate how long-distance connections in the ENS operate and study how transplanted stem cells can repair specific lesions in the mouse ENS. Lastly, we will use biopsies and resection specimens from Hirschsprung’s patients to study how cellular environment affects hosting transplanted induced pluripotent stem cell (iPSC) derived precursors.

To investigate enteric neurocircuitry we will use advanced live imaging and dedicated microscopy equipment. Imaging techniques have the important advantage that activity in entire cellular networks can be visualized simultaneously.

With the advent of genetically encoded optical tools, a number of older microscopy techniques have regained importance as the contrast does not have to be generated by the optical approach but arises from the expression system itself. In combination with advanced (for example 2-photon) microscopy, it is possible to leave tissues intact and study cellular activity in situ, even at high spatiotemporal resolution.

Some of the work will rely on the measurements performed on a newly developed microscope, which has an upright and inverted part that can move independently from each other.

The project will be complemented by the project on 'Stem cell therapy for the treatment of achalasia and gastroparesis' and the collaboration will ensure a successful completion of the project.

The exchange between both institutes guarantees exposure to both expert imaging as well as specific enteric stem cell technology.

The graduate researcher on this project is: Klaas van Mechelen

Supervision team

KU Leuven: Professor Dr Pieter Vanden Berghe, Professor Dr Marc Miserez

The University of Melbourne: Dr Lincon Stamp, Dr Marlene Hao