"The Enteric Nervous System in gut and brain disorders"
Organoid
Recent advances in human pluripotent stem cell or tissue-specific adult stem cell biology have fostered high-fidelity modelling of virtually any tissue in the human body. Three-dimensional (3D) cellular models offer enhanced predictivity of physiological and functional readouts than standard two-dimensional cell culture models. At TENS, we built a gastrointestinal organoid core to generate, develop and exploit 3D and dynamic model systems of the gut to understand cellular interactions and functions including the epithelium, the enteric nervous system and the microbiota.
The GALOP organoid core facility is dedicated to the generation and utilization of human and murine intestinal organoids. The expertise and resources, including a biobank of murine and human-derived organoids, technical tools (Transwell, Gut-on-chip) and analyses (permeability, 3D imaging), allow the exploitation of various intestinal organoid models to study the development of gut and ENS.
If you want to know more about TENS and our research activities, you can contact us and follow us on Twitter (@TENS_lab).
We use both adult stem cells and pluripotent stem cells to generate gastrointestinal organoids. You can check out our activity summary here:
https://youtu.be/38pClZIuYw4
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Murine and Human adult stem cell-derived organoids:
We are establishing both murine and human tissue-derived intestinal organoid culture to study epithelial barrier response to various stimuli including inflammation and microbiota. We also have created a biocollection of human derived ileal and colon organoids. This biocollection is currently being used to support several translational projects within our lab. These projects include funded regional projects (PROLIFIC), ANR projects MICROBIAUTISM (2019), TACI (2019), EEC and BBSCI (2021) and pilot projects.
Murine adult stem cell-derived organoid following Forskolin stimulation.
Human adult stem cell-derived organoids. Intestinal crypts from a patient sample were harvested and growth in 3D conditions. The resulting structures resemble a human mini gut.
2. Pluripotent stem cell-derived intestinal organoids:
We are directing the differentiation of pluripotent stem cell into human intestinal organoids. Using these techniques, we can engineer the gastrointestinal tube (Jejunum, Colon) in vivo. The resulting organoids can be complexified by tissue-engineering in the enteric nervous system. These models are useful in understanding GI tract development and maturation in humans. Several ANR projects (SyNEDI 2017; INCEPTION 2020; EEC 2021; NeuroPIMM 2021), FRM project (Regenerative Medicine) and a regional project (BOGUS – Bioregate) benefit from these technologies.
iPSC-derived human intestinal organoids cocultured with enteric nervous system (ENS) progenitor cells. Human intestinal organoids (HIOs) are human intestinal tissue produced in vitro from directed differentiation of human pluripotent stem cells (hPSCs). The HIO model can also include hPSC-derived enteric neuro-glial cells to obtain innervated intestinal organoids (HIO+ENS).
How do we make intestinal organoids from pluripotent stem cells?
https://youtu.be/NS10uCGNhas
3. Organoid-derived microphysiological systems (Organ-on-chip):
We aim to develop dynamic gut model systems to decipher the role of the intestinal microenvironment on the epithelial barrier function and the enteric nervous system. To that end, we are using top off the shelf mIcrophysiological devices, namely gut-on-chip, to address these questions.
Gut-on-chip using MIMETAS device
Members
Maxime Mahe (CRCN Inserm)
Michel Neunlist (DR Inserm)
Lisa Brossard (AI)
Philippe Aubert (IE Inserm)
Alexander Mösig – INSPIRE lab Jena, Germany
ITN EuROOC associate partner
Collaborators
Funding
Publications
-Vales S, Poling HM, Sundaram N, Helmrath MA, Mahe MM. In Vivo Human PSC-Derived Intestinal Organoids to Study Stem Cell Maintenance. Methods Mol Biol. 2020;2171:201-214. doi: 10.1007/978-1-0716-0747-3_12. PMID: 32705643. Link
-Loffet E, Brossard L, Mahe MM. Pluripotent stem cell derived intestinal organoids with an enteric nervous system. Methods Cell Biol. 2020;159:175-199. doi: 10.1016/bs.mcb.2020.04.012. Epub 2020 May 27. PMID: 32586442. Link
Leonetti D, Estéphan H, Ripoche N, Dubois N, Aguesse A, Gouard S, Brossard L, Chiavassa S, Corre I, Pecqueur C, Neunlist M, Hadchity E, Gaugler MH, Mahé MM, Paris F. Secretion of Acid Sphingomyelinase and Ceramide by Endothelial Cells Contributes to Radiation-Induced Intestinal Toxicity. (2020). Cancer research, 80(12), 2651–2662. Link
-Flatres C, Loffet É, Neunlist M & Mahé MM. [From human pluripotent stem cells to custom-made intestinal organoids]. (2019). Medecine Sciences: M/S, 35(6–7), 549–555. Link
- Workman MJ, Mahe MM*, Trisno S, Poling HM, Watson CL, Sundaram N, Chang CF, Schiesser J, Aubert P, Stanley EG, Elefanty AG, Miyaoka Y, Mandegar MA, Conklin BR, Neunlist M, Brugmann SA, Helmrath MA, Wells JM. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat Med. 2017 Jan;23(1):49-59. doi: 10.1038/nm.4233. Epub 2016 Nov 21. PubMed PMID: 27869805; PubMed Central PMCID: PMC5562951. (*Co-first author) (Nature Medicine Journal Cover) Link
- Watson CL, Mahe MM*, Múnera J, Howell JC, Sundaram N, Poling HM, Schweitzer JI, Vallance JE, Mayhew CN, Sun Y, Grabowski G, Finkbeiner SR, Spence JR, Shroyer NF, Wells JM, Helmrath MA. An in vivo model of human small intestine using pluripotent stem cells. Nat Med. 2014 Nov;20(11):1310-4. doi: 10.1038/nm.3737. Epub 2014 Oct 19. PubMed PMID: 25326803; PubMed Central PMCID: PMC4408376. (*Co-first author) (Nature Medicine Journal Cover) Link
-Mahe MM, Sundaram N, Watson CL, Shroyer NF & Helmrath MA. Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy. (2015). Journal of Visualized Experiments: JoVE, (97), doi:10.3791/52483. Link