The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Abstract

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled two active MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In the acutely demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In the post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation. Electronic supplementary material The online version of this article (10.1186/s40478-019-0779-2) contains supplementary material, which is available to authorized users.

Microglia Diversity in Health and Multiple Sclerosis

“…The transcriptional signature of microglia may one day be used to determine whether a lesion is demyelinating or remyelinating. The MS lesion exhibits marked diversity: Park and colleagues used imaging mass cytometry to examine the heterogeneity of CNS-associated macrophages and found that their diversity could be stratified based on their relative location within the MS lesion with enriched lysosomal LAMP1 or receptor tyrosine kinase MERTK expression on myeloid cells located at the lesion rim (115,116). Taken together, microglia initiate certain conserved activation patterns in diseased conditions but also, microglia exhibit several unique phenotypes likely reflecting their local environment.…”

Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis

“…In addition to CyTOF, we performed imaging CyTOF (IMC) to validate the results obtained from single-cell suspension samples. To date, IMC has been applied to identify multiple myeloid phenotypes on highly inflamed active lesions from one [36] or two [37] patients with RRMS. In this study, using IMC we could confirm phenotypic changes of myeloid cells characterized by CyTOF in active lesions compared with NAWM (from a total of seven PMS donors, Fig.…”

Progress and applications of mass cytometry in sketching immune landscapes

“…IMC is considered as a landmark development, as it allows for simultaneous profiling of up to 50 parameters in tandem with cell interaction and spatial information at subcellular resolution. Since its introduction, IMC is being rapidly adopted for various applications 41–47 . Damond et al employed IMC to investigate 1581 islets from four nondiabetic, four patients of onset type 1 diabetes, and four patients of long‐duration type 1 diabetes 44 .…”