Dissecting a stepwise principle of cellular diversification to instruct regeneration in the enteric nervous system

Projektinformationen

divENSify

ID Finanzhilfevereinbarung: 101045026

DOI

10.3030/101045026

EK-Unterschriftsdatum 8 April 2022

Startdatum 1 September 2022

Enddatum 31 August 2027

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 999 981,00

EU-Beitrag

€ 1 999 981,00

Koordiniert durch

KAROLINSKA INSTITUTET
Sweden

Periodic Reporting for period 1 - divENSify (Dissecting a stepwise principle of cellular diversification to instruct regeneration in the enteric nervous system)

Berichtszeitraum: 2022-09-01 bis 2025-02-28

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The gastrointestinal tract is equipped with an own intrinsic nervous system. Also denoted the “Brain in the Gut”, the enteric nervous system (ENS) acts independently of the central nervous system (CNS) by virtue of its 500 million neurons and glia that organize in full circuits across the intestines. Deficiencies within the ENS contribute to congenital, degenerative and inflammatory disorders that lack satisfactory treatment. Recently, it has been shown that enteric glia cells can convert into neurons following injury or disease, igniting hope for the development of regenerative therapies targeting gut disorders. Recovery, however, will depend on achieving a balanced neuronal constitution, emphasising the importance to define enteric neuron types and understand their development. My lab has used transcriptomics (gene expression analysis) to establish the cellular composition of the ENS in the murine gut, identifying 12 subclasses of neurons. Further transcriptome analysis at embryonic stages revealed that enteric stem cells undergoing differentiation initially only undertake one out of two neuronal identities and thereafter diversify further to other classes through identity conversions. divENSify builds on these fundamental discoveries and aims to further explore both developmental and regenerative processes in the mouse ENS. More specifically, in the first part of the project we aim to determine the detailed gene regulatory networks that governs the identity acquisition in the developing ENS by further transcriptomic (gene expression) and epigenetic (gene accessibility) analysis as well as in utero (fetal) gene manipulation experiments. In the second part of divENSify, we are deducing the innate ability of the ENS to regenerate and ask which neuron types can be generated, and whether differentiation occurs through similar mechanisms as observed during the embryonic development. In the very last part of divENSify we will attempt to generate specific neuron types in the adult gut guided by information gained from previous subprojects.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

We have to date performed extensive transcriptome (gene expression) and epigenetic (gene accessibility) profiling encompassing the mouse gut development. Our data suggest coherent developmental mechanisms at early and late stages as well as between different regions of the gut. We have performed functional testing of transcription factors, indicating specific roles in either general differentiation of stem cells to neurons or the diversification of neuron identities. Implementation of new mouse models to study the differentiation of glia to neurons in the adult gut is ongoing as well as spatial transcriptomic methods, which would allow the determination of gene expression directly in developing and adult gut tissue.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

In this midterm report we have met some goals set up for divENSify such as a transcriptional cell atlas of the developing ENS, optimization of an in utero gene manipulation technology and implementation of regenerative animal models in the ENS. We expect that these methods will be widely used by the research community to further the general knowledge of the development and regeneration within the ENS. By the end of the project we expect that we will transform our comprehension of neuron identity acquisition in the embryonic and adult gut and provide proof-of-principle experiments that open for regenerative therapy of neurological gut disorders.