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Embigin is a fibronectin receptor that affects sebaceous gland differentiation and metabolism

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Kalle Sipilä, Emanuel Rognoni, Johanna Jokinen, Mukul Tewary, Matteo Vietri Rudan, Salli Talvi, Ville Jokinen, Käthe M. Dahlström, Kif Liakath-Ali, Atefeh Mobasseri, Xinyi Du-Harpur, Jarmo Käpylä, Stephen L. Nutt, Tiina A. Salminen, Jyrki Heino, Fiona M. Watt

Original languageEnglish
Pages (from-to)1453-1465.e7
JournalDevelopmental Cell
Volume57
Issue number12
DOIs
Published20 Jun 2022

Bibliographical note

Funding Information: We would like to thank Dr Annamari Torittu, Simon Broad, Matteo Battilocchi, and Maria Tuominen for technical assistance. We would also like to thank Dr Ilkka Miinalainen as well as the expertise of Biocenter Oulu Electron Microscopy core facility, a member of Biocenter Finland, for performing immunoelectron microscopy. We thank the bioinformatics (J.V. Lehtonen), translational activities, and structural biology (FINStruct) infrastructure support from Biocenter Finland and CSC IT Center for Science for computational infrastructure support at the Structural Bioinformatics Laboratory, (SBL) Å̊bo Akademi University. We thank Sergi Garcia-Manyes, Department of Physics and Randall Institute of Cell and Molecular Biophysics, King’s College London, and his lab for help with the AFM measurements. F.M.W. gratefully acknowledges financial support from Cancer Research UK ( C219/A23522 ), the Medical Research Council ( G1100073 ), and the Wellcome Trust ( 096540/Z/11/Z ). We are also grateful for funding from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre (BRC) award to Guy’s & St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust , Sigrid Jusélius Foundation , and The Finnish Foundation for Cardiovascular Research . K.S. was supported by the postdoctoral fellowship of the Finnish Cultural Foundation , and M.T. was supported by a Marie Curie Fellowship, EU . S.L.N. was supported by a grant from National Health and Medical Research Council, Australia (# 1155342 ). Funding Information: We would like to thank Dr Annamari Torittu, Simon Broad, Matteo Battilocchi, and Maria Tuominen for technical assistance. We would also like to thank Dr Ilkka Miinalainen as well as the expertise of Biocenter Oulu Electron Microscopy core facility, a member of Biocenter Finland, for performing immunoelectron microscopy. We thank the bioinformatics (J.V. Lehtonen), translational activities, and structural biology (FINStruct) infrastructure support from Biocenter Finland and CSC IT Center for Science for computational infrastructure support at the Structural Bioinformatics Laboratory, (SBL) Å̊bo Akademi University. We thank Sergi Garcia-Manyes, Department of Physics and Randall Institute of Cell and Molecular Biophysics, King's College London, and his lab for help with the AFM measurements. F.M.W. gratefully acknowledges financial support from Cancer Research UK (C219/A23522), the Medical Research Council (G1100073), and the Wellcome Trust (096540/Z/11/Z). We are also grateful for funding from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre (BRC) award to Guy's & St Thomas’ National Health Service Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust, Sigrid Jusélius Foundation, and The Finnish Foundation for Cardiovascular Research. K.S. was supported by the postdoctoral fellowship of the Finnish Cultural Foundation, and M.T. was supported by a Marie Curie Fellowship, EU. S.L.N. was supported by a grant from National Health and Medical Research Council, Australia (#1155342). K.S. conceived the study and designed the experiments with inputs from J.H. and F.M.W. K.S. E.R. J.J. S.T. V.J. K.L.-A. A.M. and J.K. performed experiments. K.S. analyzed the data, X.D.-H. helped with the analysis of scRNA-seq data, and M.V.R. helped with the Operetta analysis. K.M.D. and T.A.S. performed structural analysis. M.T. and K.S. created the computational model of SG expansion. S.L.N. provided the anti-EMB antibody. K.S. F.M.W. and J.H. wrote the manuscript with inputs from all the authors. V.J. is currently an employee at Experimentica, Kuopio, 70210, Finland. K.M.D. is currently an employee at Orion Oyj, Espoo, 02200, Finland. A.M. is currently an employee at CN Bio Innovations Cambridge, CB40XL, UK. Publisher Copyright: © 2022 The Author(s)

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Abstract

Stem cell renewal and differentiation are regulated by interactions with the niche. Although multiple cell populations have been identified in distinct anatomical compartments, little is known about niche-specific molecular factors. Using skin as a model system and combining single-cell RNA-seq data analysis, immunofluorescence, and transgenic mouse models, we show that the transmembrane protein embigin is specifically expressed in the sebaceous gland and that the number of embigin-expressing cells is negatively regulated by Wnt. The loss of embigin promotes exit from the progenitor compartment and progression toward differentiation, and also compromises lipid metabolism. Embigin modulates sebaceous niche architecture by affecting extracellular matrix organization and basolateral targeting of monocarboxylate transport. We discover through ligand screening that embigin is a direct fibronectin receptor, binding to the N-terminal fibronectin domain without impairing integrin function. Our results solve the long-standing question of how embigin regulates cell adhesion and demonstrate a mechanism that couples adhesion and metabolism.

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