[en] The blood-brain barrier (BBB) protects the central nervous system (CNS) from harmful blood-borne factors. Although BBB dysfunction is a hallmark of several neurological disorders, therapies to restore BBB function are lacking. An attractive strategy is to repurpose developmental BBB regulators, such as Wnt7a, into BBB-protective agents. However, safe therapeutic use of Wnt ligands is complicated by their pleiotropic Frizzled signaling activities. Taking advantage of the Wnt7a/b-specific Gpr124/Reck co-receptor complex, we genetically engineered Wnt7a ligands into BBB-specific Wnt activators. In a "hit-and-run" adeno-associated virus-assisted CNS gene delivery setting, these new Gpr124/Reck-specific agonists protected BBB function, thereby mitigating glioblastoma expansion and ischemic stroke infarction. This work reveals that the signaling specificity of Wnt ligands is adjustable and defines a modality to treat CNS disorders by normalizing the BBB.
Disciplines :
Laboratory medicine & medical technology
Author, co-author :
MARTIN, Maud ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Vermeiren, Simon; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Bostaille, Naguissa ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Eubelen, Marie ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Spitzer, Daniel; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Vermeersch, Marjorie; Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Université de Mons, Gosselies B-6041, Belgium
Profaci, Caterina P ; Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA
Pozuelo, Elisa; Laboratory of Neurophysiology, ULB Neuroscience Institute, Université libre de Bruxelles, Brussels B-1070, Belgium
Toussay, Xavier ; Ottawa Hospital Research Institute, Neuroscience Program, Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Faculty of Medicine, Ottawa, Ontario, Canada
Raman-Nair, Joanna; Ottawa Hospital Research Institute, Neuroscience Program, Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Faculty of Medicine, Ottawa, Ontario, Canada
Tebabi, Patricia; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
America, Michelle; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
De Groote, Aurélie; Laboratory of Neurophysiology, ULB Neuroscience Institute, Université libre de Bruxelles, Brussels B-1070, Belgium
Sanderson, Leslie E ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Cabochette, Pauline ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Germano, Raoul F V ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Torres, David ; Institut d'Immunologie Médicale, Université libre de Bruxelles, Gosselies, Belgium
Boutry, Sébastien ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Chimie générale, organique et biomédicale ; Université de Mons - UMONS > Unités externes > Center for Microscopy and Molecular Imaging
De Kerchove D'exaerde, Alban ; Université libre de Bruxelles > ULB Neuroscience Institute > Laboratory of Neurophysiology
Bellefroid, Eric ; Laboratory of Developmental Genetics, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium
Phoenix, Timothy N ; Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
Devraj, Kavi ; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Lacoste, Baptiste ; Ottawa Hospital Research Institute, Neuroscience Program, Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, Faculty of Medicine, Ottawa, Ontario, Canada
Daneman, Richard ; Departments of Pharmacology and Neurosciences, University of California, San Diego, La Jolla, CA, USA
Liebner, Stefan ; Institute of Neurology (Edinger Institute), University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
Vanhollebeke, Benoit ; Laboratory of Neurovascular Signaling, Department of Molecular Biology, ULB Neuroscience Institute, Université libre de Bruxelles, Gosselies B-6041, Belgium ; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Wavre, Belgium
Engineered Wnt ligands enable blood-brain barrier repair in neurological disorders.
Publication date :
2022
Journal title :
Science
ISSN :
0036-8075
eISSN :
1095-9203
Publisher :
American Association for the Advancement of Science, United States
Volume :
375
Issue :
6582
Pages :
eabm4459
Peer reviewed :
Peer Reviewed verified by ORBi
Research institute :
Biosciences R550 - Institut des Sciences et Technologies de la Santé
Funding text :
M.E., and N.B. are FRIA fellows, A.D.G. is FNRS-L'Oreal fellow, and S.V. and P.C. are postdoctoral researchers of the FRS-FNRS. Work in the B.V. laboratory is supported by the FNRS (MIS F.4543.15), the Concerted Research Action, the Fondation ULB, the H2020 ITN “BtRAIN,” the Queen Elisabeth Medical Foundation, the FRFSWELBIO (CR-2017S-05R), and the ERC (Ctrl-BBB 865176). Also supported by DFG grant LI 911/5-1, LI 911/7-1, the Excellence Cluster Cardio-Pulmonary Institute, the H2020 ITN “BtRAIN,” the DZHK, and the LOEWE CePTER Epilepsy Research Center of the state Hesse (S.L. and K.D.) and by Heart and Stroke Foundation of Canada grant G-17-0018290, Canadian Institute of Health Research grant 388805, and New Frontiers Research Funds-Exploration grant NFRFE-2019-00641 (B.L.). A.d.K.d'E. is research director of FRS-FNRS, supported by FRS-FNRS and the Fondation Clerdent. The Center for Microscopy and Molecular Imaging is supported by the European Regional Development Fund and the Walloon Region.
B. Obermeier, R. Daneman, R. M. Ransohoff, Development, maintenance and disruption of the blood-brain barrier. Nat. Med. 19, 1584-1596 (2013). doi: 10.1038/nm.3407; pmid: 24309662
B. W. Chow, C. Gu, The molecular constituents of the blood-brain barrier. Trends Neurosci. 38, 598-608 (2015). doi: 10.1016/j.tins.2015.08.003; pmid: 26442694
Z. Zhao, A. R. Nelson, C. Betsholtz, B. V. Zlokovic, Establishment and Dysfunction of the Blood-Brain Barrier. Cell 163, 1064-1078 (2015). doi: 10.1016/j.cell.2015.10.067; pmid: 26590417
M. D. Sweeney, Z. Zhao, A. Montagne, A. R. Nelson, B. V. Zlokovic, Blood-Brain Barrier: From Physiology to Disease and Back. Physiol. Rev. 99, 21-78 (2019). doi: 10.1152/physrev.00050.2017; pmid: 30280653
C. P. Profaci, R. N. Munji, R. S. Pulido, R. Daneman, The blood-brain barrier in health and disease: Important unanswered questions. J. Exp. Med. 217, e20190062 (2020). doi: 10.1084/jem.20190062; pmid: 32211826
U. Lendahl, P. Nilsson, C. Betsholtz, Emerging links between cerebrovascular and neurodegenerative diseases-a special role for pericytes. EMBO Rep. 20, e48070 (2019). doi: 10.15252/embr.201948070; pmid: 31617312
S. Liebner et al., Wnt/b-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409-417 (2008). doi: 10.1083/jcb.200806024; pmid: 18955553
J. M. Stenman et al., Canonical Wnt signaling regulates organ-specific assembly and differentiation of CNS vasculature. Science 322, 1247-1250 (2008). doi: 10.1126/science.1164594; pmid: 19023080
R. Daneman et al., Wnt/b-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl. Acad. Sci. U.S.A. 106, 641-646 (2009). doi: 10.1073/pnas.0805165106; pmid: 19129494
Y. Wang et al., Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity. Cell 151, 1332-1344 (2012). doi: 10.1016/j.cell.2012.10.042; pmid: 23217714
Y. Zhou et al., Canonical WNT signaling components in vascular development and barrier formation. J. Clin. Invest. 124, 3825-3846 (2014). doi: 10.1172/JCI76431; pmid: 25083995
M. Reis et al., Endothelial Wnt/b-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression. J. Exp. Med. 209, 1611-1627 (2012). doi: 10.1084/jem.20111580; pmid: 22908324
J. E. Lengfeld et al., Endothelial Wnt/b-catenin signaling reduces immune cell infiltration in multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A. 114, E1168-E1177 (2017). doi: 10.1073/pnas.1609905114; pmid: 28137846
J. Chang et al., Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat. Med. 23, 450-460 (2017). doi: 10.1038/nm.4309; pmid: 28288111
C. Y. Janda, D. Waghray, A. M. Levin, C. Thomas, K. C. Garcia, Structural basis of Wnt recognition by Frizzled. Science 337, 59-64 (2012). doi: 10.1126/science.1222879; pmid: 22653731
R. Nusse, H. Clevers, Wnt/b-Catenin Signaling, Disease, and Emerging Therapeutic Modalities. Cell 169, 985-999 (2017). doi: 10.1016/j.cell.2017.05.016; pmid: 28575679
B. Vanhollebeke et al., Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/b-catenin pathway during brain angiogenesis. eLife 4, e06489 (2015). doi: 10.7554/eLife.06489; pmid: 26051822
C. Cho, P. M. Smallwood, J. Nathans, Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. Neuron 95, 1056-1073.e5 (2017). doi: 10.1016/j.neuron.2017.07.031; pmid: 28803732
M. Eubelen et al., A molecular mechanism for Wnt ligand-specific signaling. Science 361, eaat1178 (2018). doi: 10.1126/science.aat1178; pmid: 30026314
M. Vallon et al., A RECK-WNT7 Receptor-Ligand Interaction Enables Isoform-Specific Regulation of Wnt Bioavailability. Cell Rep. 25, 339-349.e9 (2018). doi: 10.1016/j.celrep.2018.09.045; pmid: 30304675
C. Cho, Y. Wang, P. M. Smallwood, J. Williams, J. Nathans, Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development. eLife 8, e47300 (2019). doi: 10.7554/eLife.47300; pmid: 31225798
X. Zhang et al., Tiki1 is required for head formation via Wnt cleavage-oxidation and inactivation. Cell 149, 1565-1577 (2012). doi: 10.1016/j.cell.2012.04.039; pmid: 22726442
X. Zhang et al., Notum is required for neural and head induction via Wnt deacylation, oxidation, and inactivation. Dev. Cell 32, 719-730 (2015). doi: 10.1016/j.devcel.2015.014; pmid: 25771893
H. Li et al., RECK in Neural Precursor Cells Plays a Critical Role in Mouse Forebrain Angiogenesis. iScience 19, 559-571 (2019). doi: 10.1016/j.isci.2019.08.009; pmid: 31445376
S. Eisa-Beygi, G. Hatch, S. Noble, M. Ekker, T. W. Moon, The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway regulates developmental cerebral-vascular stability via prenylation-dependent signalling pathway. Dev. Biol. 373, 258-266 (2013). doi: 10.1016/j.ydbio.2012.11.024; pmid: 23206891
K. Y. Chan et al., Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172-1179 (2017). doi: 10.1038/nn.4593; pmid: 28671695
N. A. Jessen, A. S. F. Munk, I. Lundgaard, M. Nedergaard, The Glymphatic System: A Beginner's Guide. Neurochem. Res. 40, 2583-2599 (2015). doi: 10.1007/s11064-015-1581-6; pmid: 25947369
S. Maretto et al., Mapping Wnt/b-catenin signaling during mouse development and in colorectal tumors. Proc. Natl. Acad. Sci. U.S.A. 100, 3299-3304 (2003). doi: 10.1073/pnas.0434590100; pmid: 12626757
C. Liu, Y. Wang, P. M. Smallwood, J. Nathans, An essential role for Frizzled5 in neuronal survival in the parafascicular nucleus of the thalamus. J. Neurosci. 28, 5641-5653 (2008). doi: 10.1523/JNEUROSCI.1056-08.2008; pmid: 18509025
M. Sahores, A. Gibb, P. C. Salinas, Frizzled-5, a receptor for the synaptic organizer Wnt7a, regulates activity-mediated synaptogenesis. Development 137, 2215-2225 (2010). doi: 10.1242/dev.046722; pmid: 20530549
M. Corada et al., Fine-Tuning of Sox17 and Canonical Wnt Coordinates the Permeability Properties of the Blood-Brain Barrier. Circ. Res. 124, 511-525 (2019). doi: 10.1161/CIRCRESAHA.118.313316; pmid: 30591003
T. N. Phoenix et al., Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell 29, 508-522 (2016). doi: 10.1016/j.ccell.2016.03.002; pmid: 27050100
A. Griveau et al., A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment. Cancer Cell 33, 874-889.e7 (2018). doi: 10.1016/j.ccell.2018.03.020; pmid: 29681511
A. Ben-Zvi et al., Mfsd2a is critical for the formation and function of the blood-brain barrier. Nature 509, 507-511 (2014). doi: 10.1038/nature13324; pmid: 24828040
R.-I. Kestner et al., Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice. Front. Neurosci. 14, 280 (2020). doi: 10.3389/fnins.2020.00280; pmid: 32300291
J. H. Griffin, J. A. Fernández, P. D. Lyden, B. V. Zlokovic, Activated protein C promotes neuroprotection: Mechanisms and translation to the clinic. Thromb. Res. 141 (Suppl 2), S62-S64 (2016). doi: 10.1016/S0049-3848(16)30368-1; pmid: 27207428
S. A. Lewandowski, L. Fredriksson, D. A. Lawrence, U. Eriksson, Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders. Pharmacol. Ther. 167, 108-119 (2016). doi: 10.1016/j.pharmthera.2016.07.016; pmid: 27524729
R. N. Munji et al., Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood-brain barrier dysfunction module. Nat. Neurosci. 22, 1892-1902 (2019). doi: 10.1038/s41593-019-0497-x; pmid: 31611708
