Characteristics of Blood-brain Barrier Heterogeneity Between Brain Regions Revealed by Profiling Vascular and Perivascular Cells

Overview

Journal Nat Neurosci

Date 2024 Aug 29

PMID 39210068

Authors

Sarah J Pfau

Urs H Langen

Theodore M Fisher

Indumathi Prakash

Faheem Nagpurwala

Ricardo A Lozoya

Wei-Chung Allen Lee

Zhuhao Wu

Chenghua Gu

Affiliations

Soon will be listed here.

Abstract

The blood-brain barrier (BBB) protects the brain and maintains neuronal homeostasis. BBB properties can vary between brain regions to support regional functions, yet how BBB heterogeneity occurs is poorly understood. Here, we used single-cell and spatial transcriptomics to compare the mouse median eminence, one of the circumventricular organs that has naturally leaky blood vessels, with the cortex. We identified hundreds of molecular differences in endothelial cells (ECs) and perivascular cells, including astrocytes, pericytes and fibroblasts. Using electron microscopy and an aqueous-based tissue-clearing method, we revealed distinct anatomical specializations and interaction patterns of ECs and perivascular cells in these regions. Finally, we identified candidate regionally enriched EC-perivascular cell ligand-receptor pairs. Our results indicate that both molecular specializations in ECs and unique EC-perivascular cell interactions contribute to BBB functional heterogeneity. This platform can be used to investigate BBB heterogeneity in other regions and may facilitate the development of central nervous system region-specific therapeutics.

Citing Articles

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics-Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Baraniuk J Int J Mol Sci. 2025; 26(3).

PMID: 39941050 PMC: 11818353. DOI: 10.3390/ijms26031282.

Immune control of brain physiology.

Kovacs M, Dominguez-Belloso A, Ali-Moussa S, Deczkowska A Nat Rev Immunol. 2025; .

PMID: 39890999 DOI: 10.1038/s41577-025-01129-6.

Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases.

Garcia F, Heiman M Mol Neurodegener. 2025; 20(1):13.

PMID: 39881338 PMC: 11780804. DOI: 10.1186/s13024-025-00799-z.

Transcriptional profile of the rat cardiovascular system at single-cell resolution.

Arduini A, Fleming S, Xiao L, Hall A, Akkad A, Chaffin M Cell Rep. 2024; 44(1):115091.

PMID: 39709602 PMC: 11781962. DOI: 10.1016/j.celrep.2024.115091.

Aberrant neurodevelopment in human iPS cell-derived models of Alexander disease.

Matusova Z, Dykstra W, de Pablo Y, Zetterdahl O, Canals I, van Gelder C Glia. 2024; 73(1):57-79.

PMID: 39308436 PMC: 11660530. DOI: 10.1002/glia.24618.

References

Kalucka J, de Rooij L, Goveia J, Rohlenova K, Dumas S, Meta E . Single-Cell Transcriptome Atlas of Murine Endothelial Cells. Cell. 2020; 180(4):764-779.e20. DOI: 10.1016/j.cell.2020.01.015. View

Duda D, Duyverman A, Kohno M, Snuderl M, Steller E, Fukumura D . Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci U S A. 2010; 107(50):21677-82. PMC: 3003109. DOI: 10.1073/pnas.1016234107. View

Kaplan L, Chow B, Gu C . Neuronal regulation of the blood-brain barrier and neurovascular coupling. Nat Rev Neurosci. 2020; 21(8):416-432. PMC: 8934575. DOI: 10.1038/s41583-020-0322-2. View

Almaca J, Weitz J, Rodriguez-Diaz R, Pereira E, Caicedo A . The Pericyte of the Pancreatic Islet Regulates Capillary Diameter and Local Blood Flow. Cell Metab. 2018; 27(3):630-644.e4. PMC: 5876933. DOI: 10.1016/j.cmet.2018.02.016. View

Vanlandewijck M, He L, Mae M, Andrae J, Ando K, Del Gaudio F . A molecular atlas of cell types and zonation in the brain vasculature. Nature. 2018; 554(7693):475-480. DOI: 10.1038/nature25739. View

Li Q, Cheng Z, Zhou L, Darmanis S, Neff N, Okamoto J . Developmental Heterogeneity of Microglia and Brain Myeloid Cells Revealed by Deep Single-Cell RNA Sequencing. Neuron. 2019; 101(2):207-223.e10. PMC: 6336504. DOI: 10.1016/j.neuron.2018.12.006. View

Travaglini K, Nabhan A, Penland L, Sinha R, Gillich A, Sit R . A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature. 2020; 587(7835):619-625. PMC: 7704697. DOI: 10.1038/s41586-020-2922-4. View

Brinks J, van Dijk E, Klaassen I, Schlingemann R, Kielbasa S, Emri E . Exploring the choroidal vascular labyrinth and its molecular and structural roles in health and disease. Prog Retin Eye Res. 2021; 87:100994. DOI: 10.1016/j.preteyeres.2021.100994. View

Tong S, Ji Q, Du Y, Zhu X, Zhu C, Zhou Y . Sfrp5/Wnt Pathway: A Protective Regulatory System in Atherosclerotic Cardiovascular Disease. J Interferon Cytokine Res. 2019; 39(8):472-482. PMC: 6660834. DOI: 10.1089/jir.2018.0154. View

10.

Wang Y, Smallwood P, Williams J, Nathans J . A mouse model for kinesin family member 11 (Kif11)-associated familial exudative vitreoretinopathy. Hum Mol Genet. 2020; 29(7):1121-1131. PMC: 7206855. DOI: 10.1093/hmg/ddaa018. View

11.

Montagne A, Barnes S, Sweeney M, Halliday M, Sagare A, Zhao Z . Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015; 85(2):296-302. PMC: 4350773. DOI: 10.1016/j.neuron.2014.12.032. View

12.

Macosko E, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M . Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015; 161(5):1202-1214. PMC: 4481139. DOI: 10.1016/j.cell.2015.05.002. View

13.

Yu S, Francois M, Huesing C, Munzberg H . The Hypothalamic Preoptic Area and Body Weight Control. Neuroendocrinology. 2017; 106(2):187-194. PMC: 6118330. DOI: 10.1159/000479875. View

14.

Hamilton T, Klinghoffer R, Corrin P, Soriano P . Evolutionary divergence of platelet-derived growth factor alpha receptor signaling mechanisms. Mol Cell Biol. 2003; 23(11):4013-25. PMC: 155222. DOI: 10.1128/MCB.23.11.4013-4025.2003. View

15.

Kobayashi H, Matsui T, Ishii S . Functional electron microscopy of the hypothalamic median eminence. Int Rev Cytol. 1970; 29:281-381. DOI: 10.1016/s0074-7696(08)60039-x. View

16.

Chi J, Wu Z, Choi C, Nguyen L, Tegegne S, Ackerman S . Three-Dimensional Adipose Tissue Imaging Reveals Regional Variation in Beige Fat Biogenesis and PRDM16-Dependent Sympathetic Neurite Density. Cell Metab. 2018; 27(1):226-236.e3. DOI: 10.1016/j.cmet.2017.12.011. View

17.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

18.

de Melo J, Miki K, Rattner A, Smallwood P, Zibetti C, Hirokawa K . Injury-independent induction of reactive gliosis in retina by loss of function of the LIM homeodomain transcription factor Lhx2. Proc Natl Acad Sci U S A. 2012; 109(12):4657-62. PMC: 3311371. DOI: 10.1073/pnas.1107488109. View

19.

Saunders A, Macosko E, Wysoker A, Goldman M, Krienen F, de Rivera H . Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain. Cell. 2018; 174(4):1015-1030.e16. PMC: 6447408. DOI: 10.1016/j.cell.2018.07.028. View

20.

Miller S, Policastro R, Sriramkumar S, Lai T, Huntington T, Ladaika C . LSD1 and Aberrant DNA Methylation Mediate Persistence of Enteroendocrine Progenitors That Support -Mutant Colorectal Cancer. Cancer Res. 2021; 81(14):3791-3805. PMC: 8513805. DOI: 10.1158/0008-5472.CAN-20-3562. View