Team 7bis

EVI CAT

Extracellular Vesicles based Intercellular Communication and their Application for Therapy

Team leader : Guillaume VAN NIEL

• A tool-box for EV

  
  To study these vesicles, we are creating original molecular tools. A first set of tools enable us to track by imaging these structures in live at subcellular scale and in vivo in a transparent model organism, the zebrafish. A second set of tools, based on optogenetic, allows us to manipulate each step of EV life-cycle, their biogenesis and their secretion in producing cells, their targeting and their functions in receiving cells. We notably employ our knowledge of the intracellular mechanisms supporting the cell biology behind EVs function to create new molecular tools.

• Master regulators of intercellular communication

  
  Using cell biology and imaging approaches, we have identified key proteins that regulates the endolysosomal compartments in which these vesicles are generated in producing cells or are finishing up accumulating in recipient cells. By connecting the respective endolysosomal system of EV producing and receiving cells, EVs create a bridge that supports an interlysosomal network that supports cell homeostasis within a tissue. A first key regulator is the tetraspanin CD63, a well-known endolysosomal protein with still elusive functions. More surprisingly, a second set of proteins are major actors of the etiology of Alzheimer’s Disease. We are decorticating the common mechanisms that these proteins regulate in particular the membrane dynamic and lipid homeostasis of endolysosomal compartments.

• Role of EVs and the interlysosomal network in tumor resilience

  
  We combine the fundamental knowledge and tools that we gather in the first two axes to investigate the relevance of the intercellular lysosomal network in age-related diseases and in particular in the inverse relationship between Glioma and AD at cellular and molecular level. Using cellular model and zebrafish model of both pathologies we investigate the role of CD63 but also key actors of AD etiology in the regulation of the intercellular lysosomal network with a focus on its role in clearance and trophic support that would contribute to tumor development and recurrence after therapy.

• Zebrafish as preclinical model for Therapeutic EVs

  
  EVs provide new sources of non-invasive biomarkers as their composition and secretion in biofluids reflect the physio-pathological state of their cell of origin, they. Their capacity to target specific cell types and induce phenotypical changes also establish them as potent new drug nano-vehicles.
  
  We establish the zebrafish as a relevant pre-clinical model to assess the therapeutic potential of EVs in the frame of a facility located within the IRSUN builginf. The therapeutic application of EVs comes up against a lack of knowledge of their biology and pharmacokinetic features in vivo. We have already collaborations with industrials and academic to assess the pharmacokinetic features of their functionalized EVs and their targeting and delivery capacities in our economic in vivo model at a spatiotemporal precision never reach before in vivo. In parallel, we will use of our zebrafish model to improve the isolation and characterization of cancer derived EV to use them as new source of non-invasive biomarkers. These approaches will pave the way of the harnessing of EV as drug-nanovehicles or biomarkers in personalized medecine.

  Lastest news:

  Guillaume van Niel received the Connect/NExT Senior Talent.

  https://next-isite.fr/next-talents-2/

  https://www.paysdelaloire.fr/les-aides/appel-projets-connect-talent

We are open to applications from highly motivated individuals.

Guillaume van Niel, CNRS
Guillaume.van-niel@inserm.fr

Follow us on

Twitter @guillaume_niel

Linkedinhttps://www.linkedin.com/in/guillaume-van-niel-b743a640/?originalSubdomain=fr

 

Team Members

Anaïs Bécot, Post-doctoral researcher, Paris (anais.becot@inserm.fr)
Marine Bretou, Post-doctoral researcher, Paris (marine.bretou@inserm.fr)
Maribel Lara Corona, Ph.D student Paris (maribel.lara-corona@inserm.fr)
Mickael Couty, Ph.D student, Nantes (Mickael.couty@inserm.fr)
Amandine Robac, Engineer, Paris (Amandine.robac@inserm.fr)
Ela Babursah, Engineer, Nantes (ela.babursah@inserm.fr)
Dominique Dumoulin (Technician (Dominique.dumoulin@inserm.fr)

1. Lozano-Andrés E, Enciso-Martinez A, Gijsbers A, Ridolfi A, Van Niel G, Libregts SFWM, Pinheiro C, van Herwijnen MJC, Hendrix A, Brucale M, Valle F, Peters PJ, Otto C, Arkesteijn GJA, Wauben MHM. Physical association of low density lipoprotein particles and extracellular vesicles unveiled by single particle analysis. J Extracell Vesicles. 2023 Nov;12(11):e12376. doi: 10.1002/jev2.12376.PMID: 37942918.
2. De Silva NS, Siewiera J, Alkhoury C, Nader GPF, Nadalin F, de Azevedo K, Couty M, Izquierdo HM, Bhargava A, Conrad C, Maurin M, Antoniadou K, Fouillade C, Londono-Vallejo A, Behrendt R, Bertotti K, Serdjebi C, Lanthiez F, Gallwitz L, Saftig P, Herrero-Fernández B, Saez A, González-Granado JM, van Niel G, Boissonnas A, Piel M, Manel N.Nuclear envelope disruption triggers hallmarks of aging in lung alveolar macrophages. Nat Aging. 2023 Oct;3(10):1251-1268. doi: 10.1038/s43587-023-00488-w. Epub 2023 Sep 18.PMID: 37723209
3. Bebelman MP, Setiawan IM, Bergkamp ND, van Senten JR, Crudden C, Bebelman JPM, Verweij FJ, van Niel G, Siderius M, Pegtel DM, Smit MJ.Exosomal release of the virus-encoded chemokine receptor US28 contributes to chemokine scavenging. iScience. 2023 Jul 18;26(8):107412. doi: 10.1016/j.isci.2023.107412. eCollection 2023 Aug 18.PMID: 37575190
4. Corona ML, Hurbain I, Raposo G, van Niel G. Characterization of Extracellular Vesicles by Transmission Electron Microscopy and Immunolabeling Electron Microscopy. Methods Mol Biol. 2023;2668:33-43. doi: 10.1007/978-1-0716-3203-1_4.PMID: 37140788 Free article.
5. Verweij FJ, Bebelman MP, George AE, Couty M, Bécot A, Palmulli R, Heiligenstein X, Sirés-Campos J, Raposo G, Pegtel DM, van Niel G. ER membrane contact sites support endosomal small GTPase conversion for exosome secretion. J Cell Biol. 2022 Dec 5;221(12):e202112032. doi: 10.1083/jcb.202112032. Epub 2022 Sep 22. PMID: 36136097; PMCID: PMC9507465.
6. Ferreira JV, da Rosa Soares A, Ramalho J, Máximo Carvalho C, Cardoso MH, Pintado P, Carvalho AS, Beck HC, Matthiesen R, Zuzarte M, Girão H, van Niel G, Pereira P. LAMP2A regulates the loading of proteins into exosomes. Sci Adv. 2022 doi: 10.1126/sciadv.abm1140. article.
7. van Niel G, Carter DRF, Clayton A, Lambert DW, Raposo G, Vader P. Challenges and directions in studying cell-cell communication by extracellular vesicles. Nat Rev Mol Cell Biol. 2022 doi: 10.1038/s41580-022-00460-3. Review.
8. Verweij FJ, Balaj L, Boulanger CM, Carter DRF, Compeer EB, D'Angelo G, El Andaloussi S, Goetz JG, Gross JC, Hyenne V, Krämer-Albers EM, Lai CP, Loyer X, Marki A, Momma S, Nolte-'t Hoen ENM, Pegtel DM, Peinado H, Raposo G, Rilla K, Tahara H, Théry C, van Royen ME, Vandenbroucke RE, Wehman AM, Witwer K, Wu Z, Wubbolts R, van Niel G. The power of imaging to understand extracellular vesicle biology in vivo. Nature Methods. 2021 Sep;18(9):1013-1026. doi: 10.1038/s41592-021-01206-3. Epub 2021 Aug 26. PMID: 34446922 Review.
9. Androuin A, Verweij FJ, van Niel G. Zebrafish as a preclinical model for Extracellular Vesicle-based therapeutic development. Adv Drug Deliv Rev. 2021. doi: 10.1016/j.addr.2021.05.025. Review.
10. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Follain G, Allio G, Goetz JG, Zimmermann P, Herbomel P, Del Bene F, Raposo G, van Niel G. Live Tracking of Inter-organ Communication by Endogenous Exosomes In Vivo. Dev Cell. 2019 Feb 25;48(4):573-589.e4. doi: 10.1016/j.devcel.2019.01.004. Epub 2019 Feb 7. PubMed PMID: 30745143.  
11. Théry C, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018 Nov 23;7(1):1535750. doi: 10.1080/20013078.2018.1535750. eCollection 2018. PubMed PMID: 30637094; PubMed Central PMCID: PMC6322352.
12. van Niel G, D'Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018 Jan 17. doi: 10.1038/nrm.2017.125. [Epub ahead of print] Review. PubMed PMID: 29339798.
13. Verweij FJ, Bebelman MP, Jimenez CR, Garcia-Vallejo JJ, Janssen H, Neefjes J,  Knol JC, de Goeij-de Haas R, Piersma SR, Baglio SR, Verhage M, Middeldorp JM, Zomer A, van Rheenen J, Coppolino MG, Hurbain I, Raposo G, Smit MJ, Toonen RFG, van Niel G*, Pegtel DM*. Quantifying exosome secretion from single cells reveals a  modulatory role for GPCR signaling. J Cell Biol. 2018 Jan 16. pii: jcb.201703206.doi: 10.1083/jcb.201703206. [Epub ahead of print] PubMed PMID: 29339438.(* co-last-author)
14. Bissig C, Hurbain I, Raposo G, van Niel G. PIKfyve activity regulates reformation of terminal storage lysosomes from endolysosomes. Traffic. 2017 Aug 31. PMID: 28857423
15. van Niel G, Di Cicco A, Hurbain I, Bergam P, Lo Cicero A, Dingli F, Palmulli R, Fort C, Potier MC, Loew D, Schurgers L, Raposo G and Levy D. Amyloid formation is regulated by Apolipoprotein E in endosomes. Cell Rep. Oct 2015 PMID:  26387950. Corresponding author
16. Rochin L, Hurbain I, Serneels L, Fort C, Watt B, Leblanc P, Marks MS, De Strooper B, Raposo G, van Niel G. BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10658-63. doi: 10.1073/pnas.1220748110. Epub 2013 Jun 10. PubMed PMID: 23754390; PubMed Central PMCID: PMC3696817.  
17. van Niel G, Charrin S, Simoes S, Romao M, Rochin L, Saftig P, Marks MS, Rubinstein E, Raposo G. The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev Cell. 2011 Oct 18;21(4):708-21. doi: 10.1016/j.devcel.2011.08.019. Epub 2011 Sep 29. PubMed PMID: 21962903; PubMed Central PMCID: PMC3199340.  
18. Mallegol J* and van Niel G*, Lebreton C, Lepelletier Y, Candalh C, Dugave C, Heath  JK, Raposo G, Cerf-Bensussan N, Heyman M. T84-intestinal epithelial exosomes bear MHC class II/peptide complexes potentiating antigen presentation by dendritic cells. Gastroenterology. 2007 May;132(5):1866-76. Epub 2007 Feb 22. PubMed PMID:  17484880.   (*co-first authors)
19. van Niel G, Wubbolts R, Ten Broeke T, Buschow SI, Ossendorp FA, Melief CJ, Raposo G, van Balkom BW, Stoorvogel W. Dendritic cells regulate exposure of MHC class II at their plasma membrane by oligoubiquitination. Immunity. 2006 Dec; PubMed PMID: 17174123.  
20. van Niel G, Raposo G, Candalh C, Boussac M, Hershberg R, Cerf-Bensussan N, Heyman M. Intestinal epithelial cells secrete exosome-like vesicles. Gastroenterology. 2001 Aug;121(2):337-49. PubMed PMID: 11487543. 

Fondation Alzheimer

Région Pays de la Loire      France Alzheimer