{"oa_version":"Published Version","issue":"48","scopus_import":"1","quality_controlled":"1","title":"On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias","main_file_link":[{"url":"https://www.biorxiv.org/content/10.1101/2020.04.04.025866v1","open_access":"1"}],"language":[{"iso":"eng"}],"file":[{"file_size":10381298,"content_type":"application/pdf","date_updated":"2021-11-26T06:50:09Z","file_id":"10343","creator":"cchlebak","file_name":"2020_SciAdv_Tian.pdf","relation":"main_file","success":1,"access_level":"open_access","checksum":"3ba2eca975930cdb0b1ce1ae876885a7","date_created":"2021-11-26T06:50:09Z"}],"intvolume":"         6","date_published":"2020-11-27T00:00:00Z","day":"27","tmp":{"short":"CC BY (4.0)","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","image":"/images/cc_by.png","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"year":"2020","article_type":"original","publisher":"American Association for the Advancement of Science","keyword":["multidisciplinary"],"pmid":1,"article_number":"eabc4397 ","abstract":[{"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.","lang":"eng"}],"publication":"Science Advances","publication_status":"published","_id":"10342","author":[{"last_name":"Tian","first_name":"Xiaohe","full_name":"Tian, Xiaohe"},{"full_name":"Leite, Diana M.","first_name":"Diana M.","last_name":"Leite"},{"last_name":"Scarpa","first_name":"Edoardo","full_name":"Scarpa, Edoardo"},{"last_name":"Nyberg","full_name":"Nyberg, Sophie","first_name":"Sophie"},{"last_name":"Fullstone","full_name":"Fullstone, Gavin","first_name":"Gavin"},{"first_name":"Joe","full_name":"Forth, Joe","last_name":"Forth"},{"last_name":"Matias","full_name":"Matias, Diana","first_name":"Diana"},{"last_name":"Apriceno","full_name":"Apriceno, Azzurra","first_name":"Azzurra"},{"last_name":"Poma","first_name":"Alessandro","full_name":"Poma, Alessandro"},{"last_name":"Duro-Castano","first_name":"Aroa","full_name":"Duro-Castano, Aroa"},{"full_name":"Vuyyuru, Manish","first_name":"Manish","last_name":"Vuyyuru"},{"last_name":"Harker-Kirschneck","full_name":"Harker-Kirschneck, Lena","first_name":"Lena"},{"id":"bf63d406-f056-11eb-b41d-f263a6566d8b","last_name":"Šarić","orcid":"0000-0002-7854-2139","first_name":"Anđela","full_name":"Šarić, Anđela"},{"last_name":"Zhang","full_name":"Zhang, Zhongping","first_name":"Zhongping"},{"first_name":"Pan","full_name":"Xiang, Pan","last_name":"Xiang"},{"last_name":"Fang","full_name":"Fang, Bin","first_name":"Bin"},{"last_name":"Tian","first_name":"Yupeng","full_name":"Tian, Yupeng"},{"full_name":"Luo, Lei","first_name":"Lei","last_name":"Luo"},{"first_name":"Loris","full_name":"Rizzello, Loris","last_name":"Rizzello"},{"last_name":"Battaglia","first_name":"Giuseppe","full_name":"Battaglia, Giuseppe"}],"doi":"10.1126/sciadv.abc4397","publication_identifier":{"issn":["2375-2548"]},"extern":"1","has_accepted_license":"1","type":"journal_article","date_updated":"2021-11-26T07:00:24Z","volume":6,"oa":1,"file_date_updated":"2021-11-26T06:50:09Z","user_id":"8b945eb4-e2f2-11eb-945a-df72226e66a9","ddc":["611"],"external_id":{"pmid":["33246953"]},"status":"public","month":"11","date_created":"2021-11-26T06:40:28Z","citation":{"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>.","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.","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>","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).","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>","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>.","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."},"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_processing_charge":"No"}