Molecular anatomy of adult mouse leptomeninges

Riikka Pietilä; Francesca Del Gaudio; Liqun He; Elisa Vázquez-Liébanas; Michael Vanlandewijck; Lars Muhl; Giuseppe Mocci; Katrine D. Bjørnholm; Caroline Lindblad; Alexander Fletcher-Sandersjöö; Mikael Svensson; Eric P. Thelin; Jianping Liu; A. Jantine van Voorden; Monica Torres; Salli Antila; Li Xin; Helena Karlström; Jon Storm-Mathisen; Linda Hildegard Bergersen; Aldo Moggio; Emil M. Hansson; Maria H. Ulvmar; Per Nilsson; Taija Mäkinen; Maarja Andaloussi Mäe; Kari Alitalo; Steven T. Proulx; Britta Engelhardt; Donald M. McDonald; Urban Lendahl; Johanna Andrae; Christer Betsholtz

doi:10.1016/j.neuron.2023.09.002

Molecular anatomy of adult mouse leptomeninges

Riikka Pietilä, Francesca Del Gaudio, Liqun He, Elisa Vázquez-Liébanas, Michael Vanlandewijck, Lars Muhl, Giuseppe Mocci, Katrine D. Bjørnholm, Caroline Lindblad, Alexander Fletcher-Sandersjöö, Mikael Svensson, Eric P. Thelin, Jianping Liu, A. Jantine van Voorden, Monica Torres, Salli Antila, Li Xin, Helena Karlström, Jon Storm-Mathisen, Linda Hildegard BergersenAldo Moggio, Emil M. Hansson, Maria H. Ulvmar, Per Nilsson, Taija Mäkinen, Maarja Andaloussi Mäe, Kari Alitalo, Steven T. Proulx, Britta Engelhardt, Donald M. McDonald, Urban Lendahl, Johanna Andrae, Christer Betsholtz^*

^*Corresponding author af dette arbejde

Center for Sund Aldring

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

52 Citationer (Scopus)

11 Downloads (Pure)

Abstract

Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.

Originalsprog	Engelsk
Tidsskrift	Neuron
Vol/bind	111
Udgave nummer	23
Sider (fra-til)	3745-3764.e.1-e7
Antal sider	28
ISSN	0896-6273
DOI	https://doi.org/10.1016/j.neuron.2023.09.002
Status	Udgivet - 2023

Bibliografisk note

Funding Information:
We thank Cecilia Olsson, Pia Peterson, Jana Chmielniakova, Helene Leksell, Karin Staxäng, Monika Hodik, and the BioVis core for technical assistance at Uppsala University; Sonja Gustafsson, Byambajav Buyandelger, Elisabeth Raschperger, and the single-cell core at Campus Flemingsberg (SICOF) for technical assistance at Karolinska Institutet; and Karri Niiranen, Tanja Laakkonen, Tapio Tainola, the Flow Cytometry Unit at the Helsinki Institute of Life Sciences (HiLIFE), and the Laboratory Animal Center at HiLIFE for technical assistance at the University of Helsinki. We thank Drs. Mikio Furuse, Lydia Sorokin, and Philippe Soriano for kindly providing LSR antibodies, LAMA1 antibodies, and Pdgfra-H2BGFP mice, respectively. Financial support is acknowledged as follows: Swedish Research Council (C.B. 2015-00550; U.L. 2019:00285; T.M. 2020-02692); Swedish Cancer Society (C.B. 2018/449, 2018/1154, and 211714Pj); Knut and Alice Wallenberg Foundation (C.B. 2020.0057; T.M. 2018.0218); Swedish Brain Foundation (C.B. and U.L. ALZ2019-0130 and ALZ2022-0005; U.L. F2020-0246); Erling-Persson Family Foundation (H.K. U.L. P.N. E.P.T. and C.B.); Stiftelsen för ålderssjukdomar vid KI (F.D.G. 2022:01310); Magn. Bergvalls Foundation (L.M. 2020-03735, 2021-04275, and 2022-158); Wenner-Gren foundations Fellows program (E.M.H.); Strategic Research Area Neuroscience (StratNeuro) (E.P.T.); Karolinska Institutet Funds (E.P.T. 2022-01576); Region Stockholm ALF (E.P.T. FoUI-962566); Region Stockholm Clinical Research Appointment (E.P.T. FoUI-981490); Karolinska Institutet Clinical Scientist Training Program (C.L.); Karolinska Institutet Research Internship (C.L.); Uppsala University Hospital Research Residency Program (C.L.); Strategic Research Area Stem Cells and Regeneration (StratRegen) (M.V.); KI Infrastructure Council (M.V.); The European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 743155 (BrainDrain) (K.A.); Research Council of Finland Terva Program (grant 335721) and the Finnish Brain Foundation (K.A.); Swiss National Science Foundation Grant 310030_189080 (B.E.) and CRSII5_213535 (S.P. and B.E); Research Council of Norway (RCN) Grant 214458 (L.H.B. and J.S.-M.); National Heart Lung and Blood Institute of the US National Institutes of Health (D.M. R01HL143896, R01HL059157, and R01HL127402). Computations/data handling were enabled by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) at NAISS AFFILIATED SITE/SNIC CENTRE, partially funded by Swedish Research Council through grant agreements 2022-06725 and 2018-05973. C.B. J.A. and U.L. conceived and designed the project. R.P. performed ISH, immunofluorescence, and reporter mouse analyses. F.D.G. performed reporter and TBI experiments and isolated cells for scRNA-seq analysis. L.H. performed bioinformatic analyses and constructed online databases. E.V.-L. performed immunofluorescence analyses. M.V. L.M. G.M. and J.L. performed scRNA-seq analyses. K.D.B. C.L. A.F.-S. M.S. and E.P.T. performed TBI experiments. A.J.v.V. M.T. and J.A. performed reporter and immunofluorescence analyses. S.A. performed scRNA-seq analysis of the dura mater. L.X. performed analysis of reporter mice. H.K. supervised K.D.B. J.S.-M. and L.H.B. contributed Hcar1 reporter mice at an early stage of the project. A.M. and E.M.H. generated Tcf21-CreERT2 mice. M.H.U. contributed Prox1-GFP mice. M.V. P.N. and H.K. supported scRNA-seq analysis of brain vascular fragments. T.M. contributed Cldn11-CreERT2:Ai14 mice. M.A.M. supervised E.V.-L. K.A. supervised S.A. and S.T.P. supervised L.X. C.B. R.P. L.H. F.D.G. E.V.-L. M.A.M. K.A. S.T.P. B.E. D.M.M. U.L. and J.A. interpreted the data. C.B. L.H. R.P. E.V.-L. and M.A.M. designed illustrations. C.B. U.L. and D.M.M. wrote the manuscript. All authors reviewed and edited the text. The authors declare no competing interests.

Funding Information:
We thank Cecilia Olsson, Pia Peterson, Jana Chmielniakova, Helene Leksell, Karin Staxäng, Monika Hodik, and the BioVis core for technical assistance at Uppsala University; Sonja Gustafsson, Byambajav Buyandelger, Elisabeth Raschperger, and the single-cell core at Campus Flemingsberg (SICOF) for technical assistance at Karolinska Institutet; and Karri Niiranen, Tanja Laakkonen, Tapio Tainola, the Flow Cytometry Unit at the Helsinki Institute of Life Sciences (HiLIFE), and the Laboratory Animal Center at HiLIFE for technical assistance at the University of Helsinki. We thank Drs. Mikio Furuse, Lydia Sorokin, and Philippe Soriano for kindly providing LSR antibodies, LAMA1 antibodies, and Pdgfra-H2BGFP mice, respectively. Financial support is acknowledged as follows: Swedish Research Council (C.B., 2015-00550 ; U.L., 2019:00285 ; T.M., 2020-02692 ); Swedish Cancer Society (C.B., 2018/449 , 2018/1154 , and 211714Pj ); Knut and Alice Wallenberg Foundation (C.B., 2020.0057 ; T.M., 2018.0218 ); Swedish Brain Foundation (C.B. and U.L., ALZ2019-0130 and ALZ2022-0005 ; U.L., F2020-0246 ); Erling-Persson Family Foundation (H.K., U.L., P.N., E.P.T., and C.B.); Stiftelsen för ålderssjukdomar vid KI (F.D.G., 2022:01310 ); Magn. Bergvalls Foundation (L.M., 2020-03735 , 2021-04275 , and 2022-158 ); Wenner-Gren foundations Fellows program (E.M.H.); Strategic Research Area Neuroscience (StratNeuro) (E.P.T.); Karolinska Institutet Funds (E.P.T., 2022-01576 ); Region Stockholm ALF (E.P.T., FoUI-962566 ); Region Stockholm Clinical Research Appointment (E.P.T., FoUI-981490 ); Karolinska Institutet Clinical Scientist Training Program (C.L.); Karolinska Institutet Research Internship (C.L.); Uppsala University Hospital Research Residency Program (C.L.); Strategic Research Area Stem Cells and Regeneration (StratRegen) (M.V.); KI Infrastructure Council (M.V.); The European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under grant agreement No 743155 (BrainDrain) (K.A.); Research Council of Finland Terva Program (grant 335721) and the Finnish Brain Foundation (K.A.); Swiss National Science Foundation Grant 310030_189080 (B.E.) and CRSII5_213535 (S.P. and B.E); Research Council of Norway (RCN) Grant 214458 (L.H.B. and J.S.-M.); National Heart Lung and Blood Institute of the US National Institutes of Health (D.M., R01HL143896 , R01HL059157 , and R01HL127402 ). Computations/data handling were enabled by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) and the Swedish National Infrastructure for Computing (SNIC) at NAISS AFFILIATED SITE/SNIC CENTRE, partially funded by Swedish Research Council through grant agreements 2022-06725 and 2018-05973 .

Publisher Copyright:
© 2023 The Author(s)

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10.1016/j.neuron.2023.09.002Licens: CC BY

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Citationsformater

Pietilä, R., Del Gaudio, F., He, L., Vázquez-Liébanas, E., Vanlandewijck, M., Muhl, L., Mocci, G., Bjørnholm, K. D., Lindblad, C., Fletcher-Sandersjöö, A., Svensson, M., Thelin, E. P., Liu, J., van Voorden, A. J., Torres, M., Antila, S., Xin, L., Karlström, H., Storm-Mathisen, J., ... Betsholtz, C. (2023). Molecular anatomy of adult mouse leptomeninges. Neuron, 111(23), 3745-3764.e.1-e7. https://doi.org/10.1016/j.neuron.2023.09.002

Pietilä, R, Del Gaudio, F, He, L, Vázquez-Liébanas, E, Vanlandewijck, M, Muhl, L, Mocci, G, Bjørnholm, KD, Lindblad, C, Fletcher-Sandersjöö, A, Svensson, M, Thelin, EP, Liu, J, van Voorden, AJ, Torres, M, Antila, S, Xin, L, Karlström, H, Storm-Mathisen, J, Bergersen, LH, Moggio, A, Hansson, EM, Ulvmar, MH, Nilsson, P, Mäkinen, T, Andaloussi Mäe, M, Alitalo, K, Proulx, ST, Engelhardt, B, McDonald, DM, Lendahl, U, Andrae, J & Betsholtz, C 2023, 'Molecular anatomy of adult mouse leptomeninges', Neuron, bind 111, nr. 23, s. 3745-3764.e.1-e7. https://doi.org/10.1016/j.neuron.2023.09.002

@article{9f3dfa5ea4e6429293d0c79a5e0eb595,

title = "Molecular anatomy of adult mouse leptomeninges",

abstract = "Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.",

keywords = "arachnoid barrier, arachnoid mater, brain fibroblasts, dura mater, leptomeninges, perivascular fibroblast, pia mater, single-cell RNA sequencing, traumatic brain injury, tricellular junction",

author = "Riikka Pietil{\"a} and {Del Gaudio}, Francesca and Liqun He and Elisa V{\'a}zquez-Li{\'e}banas and Michael Vanlandewijck and Lars Muhl and Giuseppe Mocci and Bj{\o}rnholm, {Katrine D.} and Caroline Lindblad and Alexander Fletcher-Sandersj{\"o}{\"o} and Mikael Svensson and Thelin, {Eric P.} and Jianping Liu and {van Voorden}, {A. Jantine} and Monica Torres and Salli Antila and Li Xin and Helena Karlstr{\"o}m and Jon Storm-Mathisen and Bergersen, {Linda Hildegard} and Aldo Moggio and Hansson, {Emil M.} and Ulvmar, {Maria H.} and Per Nilsson and Taija M{\"a}kinen and {Andaloussi M{\"a}e}, Maarja and Kari Alitalo and Proulx, {Steven T.} and Britta Engelhardt and McDonald, {Donald M.} and Urban Lendahl and Johanna Andrae and Christer Betsholtz",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

doi = "10.1016/j.neuron.2023.09.002",

language = "English",

volume = "111",

pages = "3745--3764.e.1--e7",

journal = "Neuron",

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T1 - Molecular anatomy of adult mouse leptomeninges

AU - Pietilä, Riikka

AU - Del Gaudio, Francesca

AU - He, Liqun

AU - Vázquez-Liébanas, Elisa

AU - Vanlandewijck, Michael

AU - Muhl, Lars

AU - Mocci, Giuseppe

AU - Bjørnholm, Katrine D.

AU - Lindblad, Caroline

AU - Fletcher-Sandersjöö, Alexander

AU - Svensson, Mikael

AU - Thelin, Eric P.

AU - Liu, Jianping

AU - van Voorden, A. Jantine

AU - Torres, Monica

AU - Antila, Salli

AU - Xin, Li

AU - Karlström, Helena

AU - Storm-Mathisen, Jon

AU - Bergersen, Linda Hildegard

AU - Moggio, Aldo

AU - Hansson, Emil M.

AU - Ulvmar, Maria H.

AU - Nilsson, Per

AU - Mäkinen, Taija

AU - Andaloussi Mäe, Maarja

AU - Alitalo, Kari

AU - Proulx, Steven T.

AU - Engelhardt, Britta

AU - McDonald, Donald M.

AU - Lendahl, Urban

AU - Andrae, Johanna

AU - Betsholtz, Christer

PY - 2023

Y1 - 2023

N2 - Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.

AB - Leptomeninges, consisting of the pia mater and arachnoid, form a connective tissue investment and barrier enclosure of the brain. The exact nature of leptomeningeal cells has long been debated. In this study, we identify five molecularly distinct fibroblast-like transcriptomes in cerebral leptomeninges; link them to anatomically distinct cell types of the pia, inner arachnoid, outer arachnoid barrier, and dural border layer; and contrast them to a sixth fibroblast-like transcriptome present in the choroid plexus and median eminence. Newly identified transcriptional markers enabled molecular characterization of cell types responsible for adherence of arachnoid layers to one another and for the arachnoid barrier. These markers also proved useful in identifying the molecular features of leptomeningeal development, injury, and repair that were preserved or changed after traumatic brain injury. Together, the findings highlight the value of identifying fibroblast transcriptional subsets and their cellular locations toward advancing the understanding of leptomeningeal physiology and pathology.

KW - arachnoid barrier

KW - arachnoid mater

KW - brain fibroblasts

KW - dura mater

KW - leptomeninges

KW - perivascular fibroblast

KW - pia mater

KW - single-cell RNA sequencing

KW - traumatic brain injury

KW - tricellular junction

U2 - 10.1016/j.neuron.2023.09.002

DO - 10.1016/j.neuron.2023.09.002

M3 - Journal article

C2 - 37776854

AN - SCOPUS:85174217401

SN - 0896-6273

VL - 111

SP - 3745-3764.e.1-e7

JO - Neuron

JF - Neuron

IS - 23

ER -