Single nuclei RNAseq stratifies multiple sclerosis patients into distinct white matter glial responses

Abstract

The lack of understanding as to the cellular and molecular basis of clinical and genetic heterogeneity in progressive multiple sclerosis (MS) has hindered the search for new effective therapies and biomarkers. Here, to address this gap, we analysed 740,000 single nuclei RNAseq profiles of 165 samples of white matter (WM) lesions, normal appearing WM, grey matter (GM) lesions and normal appearing GM from 55 MS patients and 28 controls. We find that gene expression changes in response to MS are highly cell-type specific in WM and GM lesions but are largely shared within an individual cell-type across lesions, following a continuum rather than discrete lesion-specific molecular programs. The major biological determinants of variability in gene expression in MS samples relate to individual patient effects, rather than to lesion types or other metadata. Using multi-omics factor analysis (MOFA+), we identify three subgroups of MS patients with distinct oligodendrocyte composition and WM glial gene expression signatures, suggestive of engagement of different pathological/regenerative processes. The discovery of these three patterns significantly advances our mechanistic understanding of progressive MS, provides a framework to use molecular biomarkers to stratify patients for best therapeutic approaches for progressive MS, and highlights the need for precision-medicine approaches to address heterogeneity among MS patients.

Seeking neuroprotection in multiple sclerosis: an ongoing challenge

“…In such lesions, there is evidence of acute axonal transections, but there is still substantial axonal presence ( 4 ). The demyelination that defines acute lesions is associated with relative preservation of oligodendrocyte (OL) cell bodies, but OL cell processes die back ( 5 , 6 ), consistent with such cells being under stress, as confirmed by single-cell molecular analyses of OLs derived from MS lesions ( 7 ). Ludwin, as early as 1981, proposed that unraveling of the spiral wrap of myelin was an early event in the development of an MS lesion ( 8 ).…”

Toward Precision Phenotyping of Multiple Sclerosis

“… 24 In this context, a recent single nucleus RNA-sequencing study of brain tissue from patients with MS and controls has uncovered 3 distinct oligodendrocyte response patterns. 25 These patterns were determined by individual patient effects only and were not associated with patient metadata such as age, disease duration, and disease category.…”

“…These massive number of modifier combinations are likely to produce a spectrum of pathway and cellular activation states along the MS-relevant pathologic axes. These may lead to a continuum of possible responses or alternatively to convergence into several major pathways as suggested by the recently described major regenerative (remyelination) patterns in MS. 25 This neuropathologic variability in turn predicts high variability of clinical presentations, which is the clinical experience with MS. It also provides new context for the clinical categories, suggesting that these are fluid rather than distinct entities and can result from different pathologic activity profiles.…”

“…This example illustrates that MRI pattern–based MS subtypes, which correlate with different pathologic processes (neuronal damage, WM tissue damage, and inflammation/demyelination), predict disease activity, disability progression, and treatment response better than conventional clinical phenotypes. Similarly, the incorporation of different oligodendrocyte response patterns 25 into the classification system and its quantification with biomarkers might be highly informative about potential responses to pre-remyelinating drugs.…”

“…However, our framework can be easily adapted to accommodate new pathobiological insights. This may include monitoring the newly postulated specific oligodendrocyte response patterns, 25 the presence of neurotoxic and neuroprotective glial subpopulations, 58 and determinants of neuroaxonal damage, such as mitochondrial dysfunction. 59 Because major efforts in MS research are currently directed at identifying biomarkers, we are hopeful that several new biomarkers will become available for clinical use in the foreseeable future that cover at least a portion of the pathologic axes activity.…”