Multi-omics and 3D-imaging reveal bone heterogeneity and unique calvaria cells in neuroinflammation

The meninges of the brain are an important component of neuroinflammatory response. Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). However, how the calvaria bone marrow is different from the other bones and whether and how it contributes to human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific alterations including increased calvaria cell numbers. Moreover, TSPO-positron-emission-tomography imaging of stroke, multiple sclerosis and neurodegenerative disease patients demonstrate disease-associated uptake patterns in the human skull, mirroring the underlying brain inflammation. Our study indicates that the calvaria is more than a physical barrier, and its immune cells may present new ways to control brain pathologies. ### Competing Interest Statement Mat.B. received speaker honoraria from GE healthcare, Roche and Life Molecular Imaging and is an advisor of Life Molecular Imaging. J. H. reports personal fees, research grants and non-financial support from Merck, Bayer, Novartis, Roche, Biogen, Celgene and non-financial support of the Guthy-Jackson Charitable Foundation; none in relation to this study. TK has received speaker honoraria and/or personal fees for advisory boards from Bayer Healthcare, Teva Pharma, Merck, Novartis, Sanofi/Genzyme, Roche and Biogen as well as grant support from Novartis and Chugai Pharma; none in relation to this study. M.K.. has been on advisory boards for Biogen, medDay Pharmaceuticals, Novartis and Sanofi, has received grant support from Sanofi and Biogen and speakers fees from Abbvie, Almirall, Biogen, medDay Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi and Teva; none in relation to this study. R.P. has received speaker honoraria, research support and consultancy fees from Janssen, Eli Lilly, Biogen, Wilmar Schwabe, Takeda, Novo Nordisk and Bayer Healthcare.