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Distinct Fibroblast Subtypes Populate Specific Brain Barriers

48 Pages Posted: 10 Nov 2022 Publication Status: Published

See all articles by Francesca Del Gaudio

Francesca Del Gaudio

Karolinska Institutet - Department of Cell and Molecular Biology

Liqun He

Uppsala University - Department of Immunology, Genetics and Pathology

Riikka Pietilä

Uppsala University - Department of Immunology, Genetics and Pathology

Michael Vanlandewijck

Karolinska Institutet - Department of Medicine; Uppsala University - Department of Immunology, Genetics and Pathology

Lars Muhl

Karolinska Institutet - Department of Medicine

Giuseppe Mocci

Karolinska Institutet - Department of Medicine

Katrine Dahl Bjørnholm

Karolinska Institutet - Division of Neurogeriatrics

Jianping Liu

Karolinska Institutet - Department of Medicine

Jantine van Voorden

Uppsala University - Department of Immunology, Genetics and Pathology

Monica Torres

Uppsala University - Department of Immunology, Genetics and Pathology

Aldo Moggio

Karolinska Institutet - Department of Medicine

Salli Antilla

University of Helsinki - Wihuri Research Institute and Translational Cancer Medicine Program

Jon Storm-Mathisen

University of Oslo - Division of Anatomy

Linda Hildegard Bergersen

University of Oslo - Brain and Muscle Energy Group

Per Nilsson

Karolinska Institutet - Division of Neurogeriatrics

Emil Hansson

Karolinska Institutet - Department of Medicine

Kari Alitalo

University of Helsinki - Wihuri Research Institute and Translational Cancer Medicine Program

Urban Lendahl

Karolinska Institutet - Department of Cell and Molecular Biology

Johanna Andrae

Uppsala University - Department of Immunology, Genetics and Pathology

Christer Betsholtz

Uppsala University - Department of Immunology, Genetics and Pathology

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Abstract

Fibroblasts in the brain and surrounding leptomeninges have been implicated in neuroinflammation and fibrotic scarring, but they likely also carry out essential physiological functions. The extent of their diversity and localizations is however less explored, and here, by combining single-cell transcriptomics with multimodal high-resolution imaging, we identify six molecularly distinct fibroblast subtypes (BFB1-6) in the adult mouse brain. Surprisingly, we found that the fibroblast subtypes contribute differentially and specifically to the brain’s various barriers toward blood and cerebrospinal fluid. Specifically, BFB1 cells make up the pia and encircle leptomeningeal, as well as brain parenchymal blood vessels. BFB2 and BFB3 cells form the inner part of the arachnoid, BFB4 cells the arachnoid barrier, and BFB5 cells the dural border. While BFB1-5 cells reside at or near non-fenestrated blood vessels, BFB6 cells align the fenestrated blood vessels of the choroid plexus and the median eminence. The six BFBs exhibit differential expression of junctional proteins, extracellular matrix components, membrane-bound drug- and solute transporters, as well as receptors and drug metabolizing enzymes, together suggesting that they hold profound specializations for physical and metabolic barrier functions.

Funding Information: Financial support is gratefully acknowledged as follows: Swedish Research Council (C.B.: 2015-00550, U.L.: 2019:00285); The Swedish Cancer Society (C.B.: 2018/449, 2018/1154, 21 1714 Pj); Knut and Alice Wallenberg Foundation (C.B.: 2015.0030, 2020.0057); The Swedish Brain Foundation (C.B. and U.L.: ALZ2019-0130, ALZ2022-0005; U.L.: F02020-0246); Innovative Medicines Initiative (C.B.: IM2PACT 807015); The Louis-Jeantet Medical Prize (C.B.); The Anders Jahre Medical Prize (C.B.); The Erling-Persson Family Foundation (U.L. P.N. and C.B.); Magn. Bergvalls Foundation (L.M.: 2020-03735 and 2021-04275); The Wenner-Gren foundations Fellows program (E.M.H).

Declaration of Interests: None to declare.

Ethics Approval Statement: All mouse experiments were conducted according to Swedish and European legislation. Ethical permits were approved by the Animal Ethics Committees in Uppsala (C115/15, 5.8.18-03029/2020) and in Stockholm (5253-2019). Experimental procedures were performed under anesthesia and all efforts were made to minimize suffering.

Keywords: brain fibroblasts, blood-brain barrier, blood-CSF barrier, arachnoid barrier, leptomeninges, choroid plexus

Suggested Citation

Del Gaudio, Francesca and He, Liqun and Pietilä, Riikka and Vanlandewijck, Michael and Muhl, Lars and Mocci, Giuseppe and Bjørnholm, Katrine Dahl and Liu, Jianping and van Voorden, Jantine and Torres, Monica and Moggio, Aldo and Antilla, Salli and Storm-Mathisen, Jon and Hildegard Bergersen, Linda and Nilsson, Per and Hansson, Emil and Alitalo, Kari and Lendahl, Urban and Andrae, Johanna and Betsholtz, Christer, Distinct Fibroblast Subtypes Populate Specific Brain Barriers. Available at SSRN: https://ssrn.com/abstract=4240422 or http://dx.doi.org/10.2139/ssrn.4240422
This version of the paper has not been formally peer reviewed.

Francesca Del Gaudio

Karolinska Institutet - Department of Cell and Molecular Biology ( email )

Liqun He

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Riikka Pietilä

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Michael Vanlandewijck

Karolinska Institutet - Department of Medicine ( email )

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Lars Muhl

Karolinska Institutet - Department of Medicine ( email )

Giuseppe Mocci

Karolinska Institutet - Department of Medicine ( email )

Katrine Dahl Bjørnholm

Karolinska Institutet - Division of Neurogeriatrics ( email )

Jianping Liu

Karolinska Institutet - Department of Medicine ( email )

Jantine Van Voorden

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Monica Torres

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Aldo Moggio

Karolinska Institutet - Department of Medicine ( email )

Salli Antilla

University of Helsinki - Wihuri Research Institute and Translational Cancer Medicine Program ( email )

Jon Storm-Mathisen

University of Oslo - Division of Anatomy ( email )

Linda Hildegard Bergersen

University of Oslo - Brain and Muscle Energy Group ( email )

Per Nilsson

Karolinska Institutet - Division of Neurogeriatrics ( email )

Emil Hansson

Karolinska Institutet - Department of Medicine ( email )

Kari Alitalo

University of Helsinki - Wihuri Research Institute and Translational Cancer Medicine Program ( email )

Urban Lendahl

Karolinska Institutet - Department of Cell and Molecular Biology ( email )

Johanna Andrae

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

Christer Betsholtz (Contact Author)

Uppsala University - Department of Immunology, Genetics and Pathology ( email )

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