1. Altered perivascular fibroblast activity precedes ALS disease onset
- Author
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Jennie Olofsson, Peter Lönnerberg, Caroline Ingre, Elena Rodriguez-Vieitez, Inci Sevval Aksoylu, Caroline Mijnsbergen, Manuela Lehmann, Jan H. Veldink, Inti von Gohren Antequera, Albert C. Ludolph, Anna Szczepińska, Stefan Wouters, Mathias Uhlén, Ulf Kläppe, Eleonora Aronica, Hermieneke Vergunst-Bosch, Anna Månberg, Julia Remnestål, Sebastian A. Lewandowski, Lwaki Ebarasi, Peter Nilsson, Aylin Domaniku, Robert A. Harris, Nathan G. Skene, Jasper J. Anink, Joke De Vocht, Eva Hedlund, Annemarie Hübers, Koen Poesen, Philip Van Damme, Marta Trusohamn, Jonathan D. Gilthorpe, Maxim De Schaepdryver, Folkert Sanders, Pathology, APH - Aging & Later Life, APH - Mental Health, and ANS - Cellular & Molecular Mechanisms
- Subjects
0301 basic medicine ,Pathology ,Transcription, Genetic ,Cell ,blood [Osteopontin] ,Disease ,blood [Amyotrophic Lateral Sclerosis] ,Superoxide Dismutase-1 ,0302 clinical medicine ,Cerebrospinal fluid ,genetics [Superoxide Dismutase] ,Medicine ,SPP1 protein, human ,Perivascular space ,Amyotrophic lateral sclerosis ,11 Medical and Health Sciences ,physiopathology [Amyotrophic Lateral Sclerosis] ,General Medicine ,Prognosis ,Col6a1 protein, human ,DNA-Binding Proteins ,genetics [Amyotrophic Lateral Sclerosis] ,medicine.anatomical_structure ,Spinal Cord ,030220 oncology & carcinogenesis ,metabolism [Collagen Type VI] ,Disease Progression ,metabolism [DNA-Binding Proteins] ,pathology [Fibroblasts] ,metabolism [Biomarkers] ,Genetic Markers ,pathology [Blood Vessels] ,medicine.medical_specialty ,Neurofilament ,genetics [Collagen Type VI] ,Immunology ,Mice, Transgenic ,pathology [Spinal Cord] ,Collagen Type VI ,Vascular Remodeling ,metabolism [RNA, Messenger] ,Article ,General Biochemistry, Genetics and Molecular Biology ,genetics [RNA, Messenger] ,03 medical and health sciences ,ultrastructure [Spinal Cord] ,Animals ,Humans ,ddc:610 ,RNA, Messenger ,pathology [Amyotrophic Lateral Sclerosis] ,Fibroblast ,Superoxide Dismutase ,business.industry ,Amyotrophic Lateral Sclerosis ,Fibroblasts ,Spinal cord ,medicine.disease ,030104 developmental biology ,Blood Vessels ,Osteopontin ,business ,Biomarkers - Abstract
Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
- Published
- 2021
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