Growth and maturation of gut and ENS during perinatal development
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The use of human pluripotent stem cells offers great avenues to generate human tissues. The understanding of intestinal development and its translation to human pluripotent stem cells, allowed the field to move forward in understanding intestinal development and gastrointestinal diseases. Our lab has developed unique model systems of the human intestine with the endeavor to study gastrointestinal physiopathology. Using human pluripotent stem cells, we were able to generate a human intestine reassembling human intestinal features including and enteric nervous system (ENS). The use of iPSCs-derived organoid models represent a real opportunity to expand our knowledge into the effect of ENS on intestinal development and toward the understanding of pathophysiological processes leading to functional gastrointestinal neuropathies. In addition, our lab is also investigating forthecoming strategies that could be used to create a fully functional intestine in vitro that could be used in conjonction with microbiota and nutrients.
Role of the enteric nervous system on human intestinal development:
We study how ENS progenitor cells, namely vagal enteric neural crest cells, regulate intestinal mesoderm cell fate including epithelial to mesoderm transition and lineage commitment to form intestinal smooth muscle and vascular tissues. We explore these processes in physiology and GI pathologies including Hirschsprung’s disease. To address this question, we produce human intestinal organoids from pluripotent stem cells with a developed ENS and laminated mesenchymal tissues. The combination of single cell sequencing and organoid models allow us to capture the underlying developmental processes at the cellular resolution.
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).
Cell atlas of human intestinal organoids derived from pluripotent stem cells (PhD student: Elise Loffet)
2. Patterning of the enteric nervous system during both neonatal and postnatal periods:
We study how exposure to luminal contents (i.e. microbiota) enhances ENS maturation and thereby gut maturation. Human GI Organoids generated from adult or pluripotent stem cell lines provide with a suitable platform to address microbiota-gut interactions. We characterize the molecular and cellular changes induced by the microbiota on the human gut in vitro and using transplanted organoids.
Metabolic modeling of enterocyte-bacteria interactions (PhD student: Anna Lambert)
3. Strategies to bioengineer human gastrointestinal tissues (organoids):
We aim to develop novel gut engineering methodologies resulting in improved clinical suitability and increased functionality following transplantation. We use 3D biofabrication approaches in combination with pluripotent stem cell differentiation to generate human tubular intestine and assess their transplant ability using unique immunocompromised murine models.
Researchers / Clinicians
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Sandrine Faure and Pascal de Santa Barbara – PHYMEDEX Montpellier
Gérard Gradwhol and Nacho Molina– IGBMC Strasbourg
Jean-Yves Hascoët and Luciano Vidal – Ecole Centrale de Nantes
Ignacio Anegon – CRTI Nantes
Nadine Cerf-Bensoussan – IMAGINE Paris
Veerle Melotte – University of Maastricht Netherland
Alexander Mösig – INSPIRE lab Jena, Germany
Michael Helmrath and Jim Wells – CCHMC Cincinnati, USA
Complete list of publications :https://www.ncbi.nlm.nih.gov/myncbi/maxime.mahe.1/bibliography/public/
-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. 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. Link
- Múnera JO, Sundaram N, Rankin SA, Hill D, Watson C, Mahe MM, Vallance JE, Shroyer NF, Sinagoga KL, Zarzoso-Lacoste A, Hudson JR, Howell JC, Chatuvedi P, Spence JR, Shannon JM, Zorn AM, Helmrath MA, Wells JM. Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling. Cell Stem Cell. 2019 May 2;24(5):829. Link
- Cortez AR, Poling HM, Brown NE, Singh A, Mahe MM, Helmrath MA. Transplantation of human intestinal organoids into the mouse mesentery: A more physiologic and anatomic engraftment site. Surgery. 2018 Oct;164(4):643-650. Link
- Poling HM, Wu D, Brown N, Baker M, Hausfeld TA, Huynh N, Chaffron S, Dunn JCY, Hogan SP, Wells JM, Helmrath MA, Mahe MM. Mechanically induced development and maturation of human intestinal organoids in vivo. Nat Biomed Eng. 2018 Jun;2(6):429-442. Link
- Mahe MM, Brown NE, Poling HM, Helmrath MA. In Vivo Model of Small Intestine. Methods Mol Biol. 2017;1597:229-245. 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. Link
- Finkbeiner SR, Hill DR, Altheim CH, Dedhia PH, Taylor MJ, Tsai YH, Chin AM, Mahe MM, Watson CL, Freeman JJ, Nattiv R, Thomson M, Klein OD, Shroyer NF, Helmrath MA, Teitelbaum DH, Dempsey PJ, Spence JR. Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo. Stem Cell Reports. 2015 Jun 3. pii: S2213-6711(15)00122-8. Link
- Mahe MM, Sundaram N, Watson CL, Shroyer NF, Helmrath MA. Establishment of human epithelial enteroids and colonoids from whole tissue and biopsy. J Vis Exp. 2015 Mar 6;(97). 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. Link