Altered perivascular fibroblast activity precedes ALS disease onset.
Anna MånbergNathan SkeneFolkert SandersMarta TrusohamnJulia RemnestålAnna SzczepińskaInci Sevval AksoyluPeter LönnerbergLwaki EbarasiStefan WoutersManuela LehmannJennie OlofssonInti von Gohren AntequeraAylin DomanikuMaxim De SchaepdryverJoke De VochtKoen PoesenMathias UhlenJasper AninkCaroline MijnsbergenHermieneke Vergunst-BoschAnnemarie HübersUlf KläppeElena Rodriguez-VieitezJonathan D GilthorpeEva HedlundRobert A HarrisEleonora AronicaPhilip Van DammeAlbert LudolphJan Herman VeldinkCaroline IngrePeter NilssonSebastian A LewandowskiPublished in: Nature medicine (2021)
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.
Keyphrases
- amyotrophic lateral sclerosis
- cerebrospinal fluid
- spinal cord
- risk factors
- single cell
- induced apoptosis
- mouse model
- cell cycle arrest
- poor prognosis
- inflammatory response
- stem cells
- magnetic resonance imaging
- gene expression
- computed tomography
- bone marrow
- genome wide
- endoplasmic reticulum stress
- signaling pathway
- cell proliferation
- cell death
- mesenchymal stem cells
- lipopolysaccharide induced
- brain injury
- oxidative stress
- electronic health record
- subarachnoid hemorrhage
- long non coding rna
- binding protein
- adverse drug