---
DOAJ_listed: '1'
OA_place: publisher
OA_type: gold
_id: '10342'
abstract:
- lang: eng
  text: The blood-brain barrier is made of polarized brain endothelial cells (BECs)
    phenotypically conditioned by the central nervous system (CNS). Although transport
    across BECs is of paramount importance for nutrient uptake as well as ridding
    the brain of waste products, the intracellular sorting mechanisms that regulate
    successful receptor-mediated transcytosis in BECs remain to be elucidated. Here,
    we used a synthetic multivalent system with tunable avidity to the low-density
    lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of
    transport across BECs. We used a combination of conventional and super-resolution
    microscopy, both in vivo and in vitro, accompanied with biophysical modeling of
    transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting
    protein syndapin-2 on fast transport via tubule formation. We show that high-avidity
    cargo biases the LRP1 toward internalization associated with fast degradation,
    while mid-avidity augments the formation of syndapin-2 tubular carriers promoting
    a fast shuttling across.
acknowledgement: 'Funding: G.B. thanks the ERC for the starting grant (MEViC 278793)
  and consolidator award (CheSSTaG 769798), EPSRC/BTG Healthcare Partnership (EP/I001697/1),
  EPSRC Established Career Fellowship (EP/N026322/1), EPSRC/SomaNautix Healthcare
  Partnership EP/R024723/1, and Children with Cancer UK for the research project (16-227).
  X.T. and G.B. thank that Anhui 100 Talent program for facilitating data sharing
  and research visits. A.D.-C. and L.R. acknowledge the Royal Society for a Newton
  fellowship and the Marie Skłodowska-Curie Actions for a European Fellowship. Author
  contributions: X.T. prepared and characterized POs, performed all the fast imaging
  in both conventional and STED microscopy, set up the initial BBB model, encapsulated
  the PtA2 in POs, and supervised the PtA2-PO animal work. D.M.L. prepared and characterized
  POs; performed all the permeability studies, PLA assays, WB and associated data
  analysis, and part of the colocalization assays; and performed experiments with
  the shRNA for knockdown of syndapin-2. E.S. prepared and characterized POs and performed
  part of colocalization assays and Cy7-labeled PO animal experiments. S.N. prepared
  and characterized POs and performed part of the colocalization and inhibition assays.
  G.F. designed, performed, and analyzed the agent-based simulations of transcytosis.
  J.F. designed the image-based algorithm to analyze the PLA data. D.M. prepared and
  characterized POs and helped with Cy7-labeled PO animal experiments. A.A. performed
  TEM imaging of the POs. A.P. and A.D.-C. synthesized the dye- and peptide-functionalized
  and pristine copolymers. M.V., L.H.-K., and A.Š. designed, performed, and analyzed
  the MD simulations. Z.Z. supervised and supported STED imaging. P.X., B.F., and
  Y.T. synthesized and characterized the PtA2 compound. L.L. performed some of the
  animal work. L.R. supported and helped with the BBB characterization. G.B. analyzed
  all fast imaging and supervised and coordinated the overall work. X.T., D.M.L.,
  E.S., and G.B. wrote the manuscript. Competing interests: The authors declare that
  part of the work is associated with the UCL spin-out company SomaNautix Ltd. Data
  and materials availability: All data needed to evaluate the conclusions in the paper
  are present in the paper and/or the Supplementary Materials. Additional data related
  to this paper may be requested from the authors.'
article_number: 'eabc4397 '
article_processing_charge: No
article_type: original
author:
- first_name: Xiaohe
  full_name: Tian, Xiaohe
  last_name: Tian
- first_name: Diana M.
  full_name: Leite, Diana M.
  last_name: Leite
- first_name: Edoardo
  full_name: Scarpa, Edoardo
  last_name: Scarpa
- first_name: Sophie
  full_name: Nyberg, Sophie
  last_name: Nyberg
- first_name: Gavin
  full_name: Fullstone, Gavin
  last_name: Fullstone
- first_name: Joe
  full_name: Forth, Joe
  last_name: Forth
- first_name: Diana
  full_name: Matias, Diana
  last_name: Matias
- first_name: Azzurra
  full_name: Apriceno, Azzurra
  last_name: Apriceno
- first_name: Alessandro
  full_name: Poma, Alessandro
  last_name: Poma
- first_name: Aroa
  full_name: Duro-Castano, Aroa
  last_name: Duro-Castano
- first_name: Manish
  full_name: Vuyyuru, Manish
  last_name: Vuyyuru
- first_name: Lena
  full_name: Harker-Kirschneck, Lena
  last_name: Harker-Kirschneck
- first_name: Anđela
  full_name: Šarić, Anđela
  id: bf63d406-f056-11eb-b41d-f263a6566d8b
  last_name: Šarić
  orcid: 0000-0002-7854-2139
- first_name: Zhongping
  full_name: Zhang, Zhongping
  last_name: Zhang
- first_name: Pan
  full_name: Xiang, Pan
  last_name: Xiang
- first_name: Bin
  full_name: Fang, Bin
  last_name: Fang
- first_name: Yupeng
  full_name: Tian, Yupeng
  last_name: Tian
- first_name: Lei
  full_name: Luo, Lei
  last_name: Luo
- first_name: Loris
  full_name: Rizzello, Loris
  last_name: Rizzello
- first_name: Giuseppe
  full_name: Battaglia, Giuseppe
  last_name: Battaglia
citation:
  ama: 'Tian X, Leite DM, Scarpa E, et al. On the shuttling across the blood-brain
    barrier via tubule formation: Mechanism and cargo avidity bias. <i>Science Advances</i>.
    2020;6(48). doi:<a href="https://doi.org/10.1126/sciadv.abc4397">10.1126/sciadv.abc4397</a>'
  apa: 'Tian, X., Leite, D. M., Scarpa, E., Nyberg, S., Fullstone, G., Forth, J.,
    … Battaglia, G. (2020). On the shuttling across the blood-brain barrier via tubule
    formation: Mechanism and cargo avidity bias. <i>Science Advances</i>. American
    Association for the Advancement of Science. <a href="https://doi.org/10.1126/sciadv.abc4397">https://doi.org/10.1126/sciadv.abc4397</a>'
  chicago: 'Tian, Xiaohe, Diana M. Leite, Edoardo Scarpa, Sophie Nyberg, Gavin Fullstone,
    Joe Forth, Diana Matias, et al. “On the Shuttling across the Blood-Brain Barrier
    via Tubule Formation: Mechanism and Cargo Avidity Bias.” <i>Science Advances</i>.
    American Association for the Advancement of Science, 2020. <a href="https://doi.org/10.1126/sciadv.abc4397">https://doi.org/10.1126/sciadv.abc4397</a>.'
  ieee: 'X. Tian <i>et al.</i>, “On the shuttling across the blood-brain barrier via
    tubule formation: Mechanism and cargo avidity bias,” <i>Science Advances</i>,
    vol. 6, no. 48. American Association for the Advancement of Science, 2020.'
  ista: 'Tian X, Leite DM, Scarpa E, Nyberg S, Fullstone G, Forth J, Matias D, Apriceno
    A, Poma A, Duro-Castano A, Vuyyuru M, Harker-Kirschneck L, Šarić A, Zhang Z, Xiang
    P, Fang B, Tian Y, Luo L, Rizzello L, Battaglia G. 2020. On the shuttling across
    the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias.
    Science Advances. 6(48), eabc4397.'
  mla: 'Tian, Xiaohe, et al. “On the Shuttling across the Blood-Brain Barrier via
    Tubule Formation: Mechanism and Cargo Avidity Bias.” <i>Science Advances</i>,
    vol. 6, no. 48, eabc4397, American Association for the Advancement of Science,
    2020, doi:<a href="https://doi.org/10.1126/sciadv.abc4397">10.1126/sciadv.abc4397</a>.'
  short: X. Tian, D.M. Leite, E. Scarpa, S. Nyberg, G. Fullstone, J. Forth, D. Matias,
    A. Apriceno, A. Poma, A. Duro-Castano, M. Vuyyuru, L. Harker-Kirschneck, A. Šarić,
    Z. Zhang, P. Xiang, B. Fang, Y. Tian, L. Luo, L. Rizzello, G. Battaglia, Science
    Advances 6 (2020).
date_created: 2021-11-26T06:40:28Z
date_published: 2020-11-27T00:00:00Z
date_updated: 2024-10-16T12:56:52Z
day: '27'
ddc:
- '611'
doi: 10.1126/sciadv.abc4397
extern: '1'
external_id:
  pmid:
  - '33246953'
file:
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  creator: cchlebak
  date_created: 2021-11-26T06:50:09Z
  date_updated: 2021-11-26T06:50:09Z
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fulldoi: https://doi.org/10.1126/sciadv.abc4397
has_accepted_license: '1'
intvolume: '         6'
issue: '48'
keyword:
- multidisciplinary
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://www.biorxiv.org/content/10.1101/2020.04.04.025866v1
month: '11'
oa: 1
oa_version: Published Version
pmid: 1
publication: Science Advances
publication_identifier:
  issn:
  - 2375-2548
publication_status: published
publisher: American Association for the Advancement of Science
quality_controlled: '1'
scopus_import: '1'
status: public
title: 'On the shuttling across the blood-brain barrier via tubule formation: Mechanism
  and cargo avidity bias'
tmp:
  image: /images/cc_by.png
  legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
  name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
  short: CC BY (4.0)
type: journal_article
user_id: 0043cee0-e5fc-11ee-9736-f83bc23afbf0
volume: 6
year: '2020'
...