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New pathway for cell communication discovered

Images of cells under a microscope.

Small lipid vesicles known as extracellular vesicles are of great interest to cell scientists since it has been discovered that they mediate intercellular communication.

Now, Professor Tom Carter's group has identified a novel pathway for the storage and release of these vesicles from vascular endothelial cells.

Working in collaboration with Dr Peter Rosenthal of the Francis Crick Institute, the group's research centred on a particular type of extracellular vesicle known as 'exosomes'. In a process called exocytosis, exosomes are released into the blood or tissues where they mediate communication between cells.

Prof Carter's group discovered that exosomes can also be released during Weibel-Palade body (WPB) exocytosis. WPBs are a specialized secretory granule containing the blood coagulation factor, von Willebrand factor, and a cocktail of pro-inflammatory molecules involved in fighting infections. Exosomes derived from WPBs appear to have a distinct molecular signature from other exosomes and that indicates that they may have a unique or specific set of functions when released into the circulation. Current efforts are focused on trying to identify those specific functions.

Prof Carter said: "We identified the lipid vesicles inside WPBs using cutting edge cryo-electron tomography techniques. Direct visualization of WPB intraluminal vesicles and their secretion as exosomes from living endothelial cells was carried out using high speed fluorescence imaging".

The paper, "Stimulated release of intraluminal vesicles from Weibel-Palade Bodies," was published in the 20 June issue of Blood. (2019) 133:2707-2717 and was accompanied by a special commentary by Pofessor Harry F. G. Heijnen of the University Medical Center Utrecht entitled “WPBs and a-granules: more and more look-alike?” Blood (2019) 133, 2634-2636.

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2019 publications

Carter T, Bierings R. (2019). WPBs: making a mark and leaving a trail. Blood. 134 (12)909-910. DOI: 10.1182/blood.2019002322

Anton Dvorzhak, Nordine Helassa, Katalin Török, Dietmar Schmitz and Rosemarie Grantyn 
Single Synapse Indicators of Impaired Glutamate Clearance Derived from Fast iGluu Imaging of Cortical Afferents in the Striatum of Normal and Huntington (Q175) Mice. Journal of Neuroscience (2019), 39, 3970-3982; DOI:

Streetley J, Fonseca AV, Turner J, Kiskin NI, Knipe L, Rosenthal PB, Carter T 
Stimulated release of intraluminal vesicles from Weibel-Palade bodies. Blood. (2019) 133:2707-2717. doi: 10.1182/blood-2018-09-874552. Epub 2019 Feb 13.

Hernando B, Swope VB, Guard S, Starner RJ, Choi K, Anwar A, Cassidy P, Leachman S, Kadekaro AL, Bennett DC, Abdel-Malek ZA
In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants. Pigment Cell Melanoma Res. (2019) 32:259-268. doi: 10.1111/pcmr.12732. Epub 2018 Sep 5

Yasmeen S, Akram BH, Hainsworth AH, Kruuse C.
Cyclic nucleotide phosphodiesterases (PDEs) and endothelial function in ischaemic stroke. A review. Cell Signal. (2019) 61:108-119. doi: 10.1016/j.cellsig.2019.05.011. Epub 2019 May 24.

Alber J, Alladi S, Bae HJ, Barton DA, Beckett LA, Bell JM, Berman SE, Biessels GJ, Black SE, Bos I, Bowman GL, Brai E, Brickman AM, Callahan BL, Corriveau RA, Fossati S, Gottesman RF, Gustafson DR, Hachinski V, Hayden KM, Helman AM, Hughes TM, Isaacs JD, Jefferson AL, Johnson SC, Kapasi A, Kern S, Kwon JC, Kukolja J, Lee A, Lockhart SN, Murray A, Osborn KE, Power MC, Price BR, Rhodius-Meester HFM, Rondeau JA, Rosen AC, Rosene DL, Schneider JA, Scholtzova H, Shaaban CE, Silva NCBS, Snyder HM, Swardfager W, Troen AM, van Veluw SJ, Vemuri P, Wallin A, Wellington C, Wilcock DM, Xie SX, Hainsworth AH.
White matter hyperintensities in vascular contributions to cognitive impairment and dementia (VCID): Knowledge gaps and opportunities. Alzheimers Dement (N Y). (2019) 5:107-117. doi: 10.1016/j.trci.2019.02.001. eCollection 2019.

Hainsworth AH. 
White matter lesions in cerebral small vessel disease: Underperfusion or leaky vessels? Neurology. (2019) 9;92:687-688. doi: 10.1212/WNL.0000000000007258. Epub 2019 Mar 13.

Berry C, Sidik N, Pereira AC, Ford TJ, Touyz RM, Kaski JC, Hainsworth AH. 
Small-Vessel Disease in the Heart and Brain: Current Knowledge, Unmet Therapeutic Need, and Future Directions. J Am Heart Assoc. (2019) 5;8:e011104. doi: 10.1161/JAHA.118.011104. No abstract available.

Vasita E, Yasmeen S, Andoh J, Bridges LR, Kruuse C, Pauls MMH, Pereira AC, Hainsworth AH. 
The cGMP-Degrading Enzyme Phosphodiesterase-5 (PDE5) in Cerebral Small Arteries of Older People. J Neuropathol Exp Neurol. (2019) 78:191-194. doi: 10.1093/jnen/nly117.

Pacitti D, Privolizzi R, Bax BE. 
Organs to Cells and Cells to Organoids: The Evolution of in vitro Central Nervous System Modelling. Front Cell Neurosci. (2019); 13:129. doi: 10.3389/fncel.2019.00129. eCollection (2019). Review.

Levene M, Bain MD, Moran NF, Nirmalananthan N, Poulton J, Scarpelli M, Filosto M, Mandel H, MacKinnon AD, Fairbanks L, Pacitti D, Bax BE. 
Safety and Efficacy of Erythrocyte Encapsulated Thymidine Phosphorylase in Mitochondrial Neurogastrointestinal Encephalomyopathy. J Clin Med. (2019) 5;8. pii: E457. doi: 10.3390/jcm8040457.

Zhang Z, Gong J, Sviderskaya EV, Wei A, Li W. 
Mitochondrial NCKX5 regulates melanosomal biogenesis and pigment production. J Cell Sci. 2019: jcs.232009. doi: 10.1242/jcs.232009. [Epub ahead of print]

Sanzà P, Evans RD, Briggs DA, Cantero M, Montoliu L, Patel S, Sviderskaya EV, Itzen A, Figueiredo AC, Seabra MC, Hume AN. 
Nucleotide exchange factor Rab3GEP requires DENN and non-DENN elements for activation and targeting of Rab27a. J Cell Sci. (2019); 132. pii: jcs212035. doi: 10.1242/jcs.212035.

Lenzi, C., Stevens, J., Osborn, D., Hannah, M. J., Bierings, R. and Carter, T. (2019). Synaptotagmin 5 regulates calcium-dependent Weibel-Palade body exocytosis in human endothelial cells. J Cell SciPMID: 30659119

Kerruth, S., Coates, C., Durst, C. D., Oertner, T. G. and Torok, K. (2019). The kinetic mechanisms of fast-decay red-fluorescent genetically-encoded calcium indicators. J Biol ChemPMID: 30651353

2018 publications

Schillemans, M., Karampini, E., van den Eshof, B. L., Gangaev, A., Hofman, M., van Breevoort, D., Meems, H., Janssen, H., Mulder, A. A., Jost, C. R. et al. (2018). Weibel-Palade Body Localized Syntaxin-3 Modulates Von Willebrand Factor Secretion From Endothelial Cells. Arterioscler Thromb Vasc Biol 38, 1549-1561. PMID: 29880488

Helassa, N., Durst, C. D., Coates, C., Kerruth, S., Arif, U., Schulze, C., Wiegert, J. S., Geeves, M., Oertner, T. G. and Torok, K. (2018). Ultrafast glutamate sensors resolve high-frequency release at Schaffer collateral synapses. Proc Natl Acad Sci U S A 115, 5594-5599. PMID: 29735711

Hernando, B., Swope, V. B., Guard, S., Starner, R. J., Choi, K., Anwar, A., Cassidy, P., Leachman, S., Kadekaro, A. L., Bennett, D. C. et al. (2018). In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants. Pigment Cell Melanoma ResPMID: 30117292

Horsburgh, K., Wardlaw, J. M., van Agtmael, T., Allan, S. M., Ashford, M. L. J., Bath, P. M., Brown, R., Berwick, J., Cader, M. Z., Carare, R. O. et al. (2018). Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology. Clin Sci (Lond) 132, 851-868. PMID: 29712883

Kim, Y. J., Osborn, D. P., Lee, J. Y., Araki, M., Araki, K., Mohun, T., Kansakoski, J., Brandstack, N., Kim, H. T., Miralles, F. et al. (2018). WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome. EMBO Rep 19, 269-289. PMID: 29263200

Laponogov, I., Pan, X. S., Veselkov, D. A., Skamrova, G. B., Umrekar, T. R., Fisher, L. M. and Sanderson, M. R. (2018). Trapping of the transport-segment DNA by the ATPase domains of a type II topoisomerase. Nat Commun 9, 2579. PMID: 29968711

Levene, M., Pacitti, D., Gasson, C., Hall, J., Sellos-Moura, M. and Bax, B. E. (2018). Validation of an Immunoassay for Anti-thymidine Phosphorylase Antibodies in Patients with MNGIE Treated with Enzyme Replacement Therapy. Mol Ther Methods Clin Dev 11, 1-8. PMID: 30294618

Pacitti, D. and Bax, B. E. (2018). The development of an in vitro cerebral organoid model for investigating the pathomolecular mechanisms associated with the central nervous system involvement in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE). Nucleosides Nucleotides Nucleic Acids, 1-15. PMID: 30587077 

Pacitti, D., Levene, M., Garone, C., Nirmalananthan, N. and Bax, B. E. (2018). Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far. Front Genet 9, 669. PMID: 30627136

Pauls, M. M., Moynihan, B., Barrick, T. R., Kruuse, C., Madigan, J. B., Hainsworth, A. H. and Isaacs, J. D. (2018). The effect of phosphodiesterase-5 inhibitors on cerebral blood flow in humans: A systematic review. J Cereb Blood Flow Metab 38, 189-203. PMID: 29256324 



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