Altered perivascular fibroblast activity precedes ALS disease onset

Abstract

Apart from the well-defined factors in neuronal cells 1 , only few reports consider that variability of sporadic ALS progression can depend on the less-defined contributions from glia 2,3 and blood vessels 4 .In this study we use an expression weighted cell-type enrichment method to infer cell activity in spinal cord samples from sporadic ALS patients and mouse models of this disease. Here we report that sporadic ALS patients present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded the 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 sporadic ALS patients. Moreover, in plasma of 574 ALS patients 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 ALS patient survival and provide a novel conceptual framework to re-evaluate definitions of ALS etiology.

Emerging roles for CNS fibroblasts in health, injury and disease

“…A preliminary study using VINE-seq to profile human vascular cells from the hippocampus and cortex of healthy individuals and patients with Alzheimer disease found dysregulation in IFNγ pathway and SMAD signalling genes in fibroblasts in Alzheimer disease 6 . In addition, in the pre-symptomatic stages of ALS, the fibroblast marker genes SPP1 and COLA6A1 are enriched and their protein products accumulate in perivascular spaces 8 . Increased expression levels of these genes predicted shorter survival times in patients with ALS, indicating that perivascular fibroblasts contribute to dysfunction early in disease progression 8 .…”

“…In addition, in the pre-symptomatic stages of ALS, the fibroblast marker genes SPP1 and COLA6A1 are enriched and their protein products accumulate in perivascular spaces 8 . Increased expression levels of these genes predicted shorter survival times in patients with ALS, indicating that perivascular fibroblasts contribute to dysfunction early in disease progression 8 .…”

“…While we focus mostly on rodent studies in this Review, perivascular fibroblasts have been detected in human tumour samples 5 and associated with the vasculature of the human brain 6 , 7 , confirming that these cells are indeed present in the human CNS. Furthermore, perivascular fibroblasts have been shown to be dysfunctional in patients with amyotrophic lateral sclerosis (ALS) 8 . More in-depth analyses of human CNS fibroblasts will determine whether these cells are potential therapeutic targets for neurological diseases.…”

In mice and humans, the brain’s blood vessels mature postnatally to acquire barrier and contractile properties

“…Our analysis therefore focused on the transcriptional signature of each vascular cell type, rather than overlaps in molecular repertoires between cell types. Several transcripts encoding ECM components were specifically expressed by FBs, confirming that these cells actively contribute to the BL (Manberg et al, 2021) and (possibly) its postnatal development because some genes were more strongly expressed on P15 than on P5 (Coelho-Santos and Shih, 2020). The recruitment of perivascular FBs and their differentiation has not previously been fully described.…”

“…Perivascular fibroblasts (FBs) are present around vessels other than capillaries (Saunders et al, 2018; Vanlandewijck et al, 2018). The FBs are highly heterogeneous and are thought to have various functions in extracellular matrix (ECM) composition, blood vessel contractility, and immune control (Manberg et al, 2021; Saunders et al, 2018). Lastly, perivascular astrocytic processes (also referred to as “endfeet”) form a continuous sheath around all the vessels (Mathiisen et al, 2010; McCaslin et al, 2011) and control several vascular properties (i.e.…”