Vassilis Pachnis

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Cellular and molecular mechanisms of enteric nervous system regeneration

Tissue homeostasis and repair depend on the ability of stem cells to replenish cellular compartments that are reduced by normal turnover, injury or disease. In the central nervous system, neural stem cells (NSCs) drive constitutive neurogenesis but in response to injury other cell types, such as glial cells, can also contribute to neural tissue repair. Regenerative neuroscience represents an exciting research field that provides fundamental insight into stem cell biology and raises the tangible possibility of harnessing the neurogenic potential of NSCs and glial cells to restore brain function following trauma or disease.

The enteric nervous system (ENS) encompasses a vast number of neurons and glia which are organised into interconnected ganglia embedded within the gut wall. The ENS regulates key aspects of digestive physiology, including gut peristalsis, secretion and blood flow, and interacts with the intestinal immune system to control host defences against pathogens. In addition, the ENS represents a relay station along the gut-brain communication axis. Given such critical roles, it is not surprising that congenital deficits of the ENS, such as Hirschsprung's Disease (or congenital megacolon) can have catastrophic or serious life-long consequences, while loss of enteric neurons and changes in connectivity (due to gut inflammation or ageing), leads to chronic and often severe gastrointestinal dysfunction. Despite such critical contributions of the ENS to gut physiology and homeostasis, very little is known about the regenerative potential of this system in adult animals.

The ENS is considered a static tissue composed of post-mitotic neurons and quiescent enteric glial cells (EGCs). However, we and others have recently demonstrated that EGCs represent a highly dynamic cellular compartment which is remodelled continuously in response to signals from the microbiota and the mucosal immune system. In addition, EGCs can undergo neuronal differentiation following chemical injury of the gut or inflammation. Despite these studies, ENS homeostasis and regeneration is poorly understood and controversial.

This project will examine the cellular and molecular mechanisms that underpin the regenerative potential of the ENS in adult animals. Using transgenic technologies, cell culture systems and molecular studies, the student will determine the identity of ENS Stem Cells (ENSCs), characterise their lineage relationships to enteric glia and ascertain the transcriptional mechanisms that control their proliferative and neurogenic potential. Specifically, genetic lineage tracing in zebrafish and mice will be used to characterise the behaviour of candidate ENSC populations under homeostatic or experimental conditions while RNA sequencing of single cells or populations of cells will be employed to determine the transcriptional profiles associated with the dynamic behaviour of ENSCs. The potential role of candidate genes in the activation and differentiation of ENSCs will be tested in available cell culture systems and by genome editing in experimental animals.

Identification of ENSCs and characterisation of their properties is essential for understanding the dynamic properties of the ENS under physiological conditions and how enteric neurons and glia respond to environmental signals (microbiota) or diseases of the gut (intestinal inflammation and cancer).

1. Lasrado, R., Boesmans, W., Kleinjung, J., Pin, C., Bell, D., Bhaw, L., McCallum, S., Zong, H., Luo, L., Clevers, H., Vanden Berghe, P. and Pachnis, V. (2017)
Lineage-dependent spatial and functional organization of the mammalian enteric nervous system.
Science  356: 722-726. PubMed abstract

2. Heanue, T. A., Boesmans, W., Bell, D. M., Kawakami, K., Vanden Berghe, P. and Pachnis, V. (2016)
A novel zebrafish ret heterozygous model of Hirschsprung disease identifies a functional role for mapk10 as a modifier of enteric nervous system phenotype severity.
PLOS Genetics  12: e1006439. PubMed abstract

3. Kabouridis, P. S., Lasrado, R., McCallum, S., Chng, S. H., Snippert, H. J., Clevers, H., Pettersson, S. and Pachnis, V. (2015)
Microbiota controls the homeostasis of glial cells in the gut lamina propria.
Neuron  85: 289-295. PubMed abstract

4. Laranjeira, C., Sandgren, K., Kessaris, N., Richardson, W., Potocnik, A., Vanden Berghe, P. and Pachnis, V. (2011)
Glial cells in the mouse enteric nervous system can undergo neurogenesis in response to injury.
Journal of Clinical Investigation  121: 3412-3424. PubMed abstract

5. Heanue, T. A. and Pachnis, V. (2007)
Enteric nervous system development and Hirschsprung's disease: advances in genetic and stem cell studies.
Nature Reviews Neuroscience  8: 466-679. PubMed abstract