Wälchli, T. et al. Shaping the brain vasculature in development and disease in the single-cell era. Nat. Rev. Neurosci. 24, 271–298 (2023).
Cho, C., Smallwood, P. M. & Nathans, J. Reck and Gpr124 are essential receptor cofactors for Wnt7a/Wnt7b-Specific signaling in mammalian CNS angiogenesis and blood-brain barrier regulation. Neuron 95, 1221–1225 (2017).
Wälchli, T. et al. Wiring the vascular network with neural cues: a CNS perspective. Neuron 87, 271–296 (2015).
Sweeney, M. D., Kisler, K., Montagne, A., Toga, A. W. & Zlokovic, B. V. The role of brain vasculature in neurodegenerative disorders. Nat. Neurosci. 21, 1318–1331 (2018).
Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008).
Kuhnert, F. et al. Essential regulation of CNS angiogenesis by the orphan G protein-coupled receptor GPR124. Science 330, 985–989 (2010).
Chang, J. et al. Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat. Med. 23, 450–460 (2017).
Anderson, K. D. et al. Angiogenic sprouting into neural tissue requires Gpr124, an orphan G protein-coupled receptor. Proc. Natl Acad. Sci. USA 108, 2807–2812 (2011).
Zhou, Y. & Nathans, J. Gpr124 controls CNS angiogenesis and blood-brain barrier integrity by promoting ligand-specific canonical wnt signaling. Dev. Cell 31, 248–256 (2014).
Carmeliet, P. Angiogenesis in health and disease. Nat. Med. 9, 653–660 (2003).
Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).
Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).
Carmeliet, P. Angiogenesis in life, disease and medicine. Nature 438, 932–936 (2005).
Quaegebeur, A., Lange, C. & Carmeliet, P. The neurovascular link in health and disease: molecular mechanisms and therapeutic implications. Neuron 71, 406–424 (2011).
Ghobrial, M. The human brain vasculature shows a distinct expression pattern of SARS-CoV-2 entry factors. Preprint at bioRxiv https://doi.org/10.1101/2020.10.10.334664 (2020).
Wälchli, T. et al. Quantitative assessment of angiogenesis, perfused blood vessels and endothelial tip cells in the postnatal mouse brain. Nat. Protoc. 10, 53–74 (2015).
Wälchli, T. et al. Hierarchical imaging and computational analysis of three-dimensional vascular network architecture in the entire postnatal and adult mouse brain. Nat. Protoc. 16, 4564–4610 (2021).
Nikolaev, S. I. et al. Somatic activating KRAS mutations in arteriovenous malformations of the brain. N. Engl. J. Med. 378, 250–261 (2018).
Wälchli, T. et al. Nogo-A is a negative regulator of CNS angiogenesis. Proc. Natl Acad. Sci. USA 110, E1943–E1952 (2013).
Wälchli, T. et al. Nogo-A regulates vascular network architecture in the postnatal brain. J. Cereb. Blood Flow Metab. 37, 614–631 (2017).
Schwab, M. et al. Nucleolin promotes angiogenesis and endothelial metabolism along the oncofetal axis in the human brain vasculature. JCI Insight 8, e143071 (2023).
Arvanitis, C. D., Ferraro, G. B. & Jain, R. K. The blood-brain barrier and blood-tumour barrier in brain tumours and metastases. Nat. Rev. Cancer 20, 26–41 (2020).
Engelhardt, B. Development of the blood-brain barrier. Cell Tissue Res. 314, 119–129 (2003).
Engelhardt, B. Blood-brain barrier differentiation. Science 334, 1652–1653 (2011).
Mancuso, M. R., Kuhnert, F. & Kuo, C. J. Developmental angiogenesis of the central nervous system. Lymphat. Res. Biol. 6, 173–180 (2008).
Daneman, R. et al. Wnt/β-catenin signaling is required for CNS, but not non-CNS, angiogenesis. Proc. Natl Acad. Sci. USA 106, 641–646 (2009).
Liebner, S. et al. Wnt/β-catenin signaling controls development of the blood-brain barrier. J. Cell Biol. 183, 409–417 (2008).
Vanlandewijck, M. et al. A molecular atlas of cell types and zonation in the brain vasculature. Nature 554, 475–480 (2018).
Majno, G. & Palade, G. E. Studies on inflammation. 1. The effect of histamine and serotonin on vascular permeability: an electron microscopic study. J. Biophys. Biochem. Cytol. 11, 571–605 (1961).
Simionescu, M., Simionescu, N. & Palade, G. E. Segmental differentiations of cell junctions in the vascular endothelium. The microvasculature. J. Cell Biol. 67, 863–885 (1975).
Han, X. et al. Construction of a human cell landscape at single-cell level. Nature 581, 303–309 (2020).
Litviňuková, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).
Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).
Garcia, F. J. et al. Single-cell dissection of the human brain vasculature. Nature 603, 893–899 (2022).
Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603, 885–892 (2022).
Winkler, E. A. et al. A single-cell atlas of the normal and malformed human brain vasculature. Science 375, eabi7377 (2022).
Crouch, E. E. et al. Ensembles of endothelial and mural cells promote angiogenesis in prenatal human brain. Cell 185, 3753–3769 (2022).
Kalucka, J. et al. Single-cell transcriptome atlas of murine endothelial cells. Cell 180, 764–779 (2020).
Marin-Padilla, M. The human brain intracerebral microvascular system: development and structure. Front. Neuroanat. 6, 38 (2012).
Saunders, N. R., Liddelow, S. A. & Dziegielewska, K. M. Barrier mechanisms in the developing brain. Front. Pharmacol. 3, 46 (2012).
Saunders, N. R., Dziegielewska, K. M., Mollgard, K. & Habgood, M. D. Physiology and molecular biology of barrier mechanisms in the fetal and neonatal brain. J. Physiol. 596, 5723–5756 (2018).
Jabbour, P. M., Tjoumakaris, S. I. & Rosenwasser, R. H. Endovascular management of intracranial aneurysms. Neurosurg. Clin. N. Am. 20, 383–398 (2009).
Xu, R., Pisapia, D. & Greenfield, J. P. Malignant transformation in glioma steered by an angiogenic switch: defining a role for bone marrow-derived cells. Cureus 8, e471 (2016).
Jain, R. K. et al. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8, 610–622 (2007).
Das, S. & Marsden, P. A. Angiogenesis in glioblastoma. N. Engl. J. Med. 369, 1561–1563 (2013).
Lorger, M., Krueger, J. S., O’Neal, M., Staflin, K. & Felding-Habermann, B. Activation of tumor cell integrin alphavbeta3 controls angiogenesis and metastatic growth in the brain. Proc. Natl Acad. Sci. USA 106, 10666–10671 (2009).
Barresi, V. Angiogenesis in meningiomas. Brain Tumor Pathol. 28, 99–106 (2011).
Picelli, S. et al. Full-length RNA-seq from single cells using Smart-seq2. Nat. Protoc. 9, 171–181 (2014).
Xie, Y. et al. Key molecular alterations in endothelial cells in human glioblastoma uncovered through single-cell RNA sequencing. JCI Insight 6, e150861 (2021).
Parab, S., Quick, R. E. & Matsuoka, R. L. Endothelial cell-type-specific molecular requirements for angiogenesis drive fenestrated vessel development in the brain. eLife 10, e64295 (2021).
Wisniewska-Kruk, J. et al. Plasmalemma vesicle-associated protein has a key role in blood-retinal barrier loss. Am. J. Pathol. 186, 1044–1054 (2016).
Bosma, E. K., van Noorden, C. J. F., Schlingemann, R. O. & Klaassen, I. The role of plasmalemma vesicle-associated protein in pathological breakdown of blood-brain and blood-retinal barriers: potential novel therapeutic target for cerebral edema and diabetic macular edema. Fluids Barriers CNS 15, 24 (2018).
Carson-Walter, E. B. et al. Plasmalemmal vesicle associated protein-1 is a novel marker implicated in brain tumor angiogenesis. Clin. Cancer Res. 11, 7643–7650 (2005).
Zhang, H. et al. Targeting endothelial cell-specific molecule 1 protein in cancer: a promising therapeutic approach. Front. Oncol. 11, 687120 (2021).
McCracken, I. R. et al. Transcriptional dynamics of pluripotent stem cell-derived endothelial cell differentiation revealed by single-cell RNA sequencing. Eur. Heart J. 41, 1024–1036 (2020).
Dieterich, L. C. et al. Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization. J. Pathol. 228, 378–390 (2012).
Huang, Z. et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc. Natl Acad. Sci. USA 118, e2023216118 (2021).
Huang, X. et al. Single-cell transcriptional profiling reveals sex and age diversity of gene expression in mouse endothelial cells. Front. Genet. 12, 590377 (2021).
Hajdarovic, K. H. et al. Single-cell analysis of the aging female mouse hypothalamus. Nat. Aging 2, 662–678 (2022).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019).
Butler, A., Hoffman, P., Smibert, P., Papalexi, E. & Satija, R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 36, 411–420 (2018).
Satija, R., Farrell, J. A., Gennert, D., Schier, A. F. & Regev, A. Spatial reconstruction of single-cell gene expression data. Nat. Biotechnol. 33, 495–502 (2015).
Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603, 885–892 (2022).
Yang, A. C. et al. Physiological blood–brain transport is impaired with age by a shift in transcytosis. Nature 583, 425–430 (2020).
Chen, M. B. et al. Brain endothelial cells are exquisite sensors of age-related circulatory cues. Cell Rep. 30, 4418–4432 (2020).
Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352–356 (2017).
He, L. et al. Analysis of the brain mural cell transcriptome. Sci. Rep. 6, 35108 (2016).
Garcia, F. J. et al. Single-cell dissection of the human brain vasculature. Nature 603, 893–899 (2022).
Schaum, N. et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature 562, 367–372 (2018).
Platel, V., Faure, S., Corre, I. & Clere, N. Endothelial-to-mesenchymal transition (EndoMT): roles in tumorigenesis, metastatic extravasation and therapy resistance. J. Oncol. 2019, 8361945–8361945 (2019).
Suvà, M. L. & Tirosh, I. The glioma stem cell model in the era of single-cell genomics. Cancer Cell 37, 630–636 (2020).
Suvà, M. L. et al. Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell 157, 580–594 (2014).
Wang, R. et al. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468, 829–833 (2010).
Ricci-Vitiani, L. et al. Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468, 824–828 (2010).
Prabavathy, D., Swarnalatha, Y. & Ramadoss, N. Lung cancer stem cells-origin, characteristics and therapy. Stem Cell Invest. 5, 6 (2018).
Lawton, M. T. et al. Brain arteriovenous malformations. Nat. Rev. Dis. Primers 1, 15008 (2015).
Malinverno, M. et al. Endothelial cell clonal expansion in the development of cerebral cavernous malformations. Nat. Commun. 10, 2761 (2019).
Orsenigo, F. et al. Mapping endothelial-cell diversity in cerebral cavernous malformations at single-cell resolution. eLife 9, e61413 (2020).
Zhu, I. et al. Modular design of synthetic receptors for programmed gene regulation in cell therapies. Cell 185, 1431–1443 (2022).
Uhlen, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).
Tang, M. et al. Evaluating single-cell cluster stability using the Jaccard similarity index. Bioinformatics 37, 2212–2214 (2021).
Sjostedt, E. et al. An atlas of the protein-coding genes in the human, pig, and mouse brain. Science 367, eaay5947 (2020).
Hodge, R. D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature 573, 61–68 (2019).
Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).
Efremova, M., Vento-Tormo, M., Teichmann, S. A. & Vento-Tormo, R. CellPhoneDB: inferring cell–cell communication from combined expression of multi-subunit ligand–receptor complexes. Nat. Protoc. 15, 1484–1506 (2020).
Farnsworth, R. H., Lackmann, M., Achen, M. G. & Stacker, S. A. Vascular remodeling in cancer. Oncogene 33, 3496–3505 (2014).
Trapnell, C. et al. The dynamics and regulators of cell fate decisions are revealed by pseudotemporal ordering of single cells. Nat. Biotechnol. 32, 381–386 (2014).
Ji, Z. & Ji, H. TSCAN: tools for single-cell analysis. R package v.1.34.0 (2022).
La Manno, G. et al. RNA velocity of single cells. Nature 560, 494–498 (2018).
Bergen, V., Lange, M., Peidli, S., Wolf, F. A. & Theis, F. J. Generalizing RNA velocity to transient cell states through dynamical modeling. Nat. Biotechnol. 38, 1408–1414 (2020).
Angerer, P. et al. destiny: diffusion maps for large-scale single-cell data in R. Bioinformatics 32, 1241–1243 (2016).
Munji, R. N. 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).
Saili, K. S. et al. Blood-brain barrier development: systems modeling and predictive toxicology. Birth Defects Res. 109, 1680–1710 (2017).
Saunders, N. R. et al. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front. Neurosci. 8, 404 (2014).
Virgintino, D. et al. Immunolocalization of tight junction proteins in the adult and developing human brain. Histochem. Cell Biol. 122, 51–59 (2004).
Daneman, R. & Prat, A. The blood-brain barrier. Cold Spring Harb. Perspect. Biol. 7, a020412 (2015).
Ben-Zvi, A. et al. Mfsd2a is critical for the formation and function of the blood–brain barrier. Nature 509, 507–511 (2014).
Ma, S. C. et al. Claudin-5 regulates blood-brain barrier permeability by modifying brain microvascular endothelial cell proliferation, migration, and adhesion to prevent lung cancer metastasis. CNS Neurosci. Ther. 23, 947–960 (2017).
Goveia, J. et al. An integrated gene expression landscape profiling approach to identify lung tumor endothelial cell heterogeneity and angiogenic candidates. Cancer Cell 37, 21–36 (2020).
Andreone, B. J. et al. Blood-brain barrier permeability is regulated by lipid transport-dependent suppression of caveolae-mediated transcytosis. Neuron 94, 581–594 (2017).
O’Brown, N. M., Megason, S. G. & Gu, C. Suppression of transcytosis regulates zebrafish blood-brain barrier function. eLife 8, e47326 (2019).
Zhao, Z., Nelson, A. R., Betsholtz, C. & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064–1078 (2015).
Kim, N. et al. Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma. Nat. Commun. 11, 2285 (2020).
Jiang, Y. Q. et al. Investigating mechanisms of response or resistance to immune checkpoint inhibitors by analyzing cell-cell communications in tumors before and after programmed cell death-1 (PD-1) targeted therapy: an integrative analysis using single-cell RNA and bulk-RNA sequencing data. Oncoimmunology 10, 1908010 (2021).