Comparing RNA‐sequencing datasets from astrocytes, oligodendrocytes, and microglia in multiple sclerosis identifies novel dysregulated genes relevant to inflammation and myelination

Abstract

Central nervous system (CNS) inflammation is a key factor in multiple sclerosis (MS). Invasion of peripheral immune cells into the CNS resulting from an unknown signal or combination of signals results in activation of resident immune cells and the hallmark feature of the disease: demyelinating lesions. These lesion sites are an amalgam of reactive peripheral and central immune cells, astrocytes, damaged and dying oligodendrocytes, and injured neurons and axons. Sustained inflammation affects cells directly located within the lesion site and further abnormalities are apparent diffusely throughout normal-appearing white matter and grey matter. It is only relatively recently, using animal models, new tissue sampling techniques, and next-generation sequencing, that molecular changes occurring in CNS resident cells have been broadly captured. Advances in cell isolation through Fluorescence Activated Cell Sorting (FACS) and laser-capture microdissection together with the emergence of single-cell sequencing have enabled researchers to investigate changes in gene expression in astrocytes, microglia, and oligodendrocytes derived from animal models of MS as well as from primary patient tissue. The contribution of some dysregulated pathways has been followed up in individual studies; however, corroborating results often go unreported between sequencing studies. To this end, we have consolidated results from numerous RNA-sequencing studies to identify and review novel patterns of differentially regulated genes and pathways occurring within CNS glial cells in MS.

Senolytic treatment depletes microglia and decreases severity of experimental autoimmune encephalomyelitis

“…Still, when considering within humans, microglia demonstrate consistent gene expression changes between aging and neurodegenerative diseases, particularly demonstrating a shared expression profile between microglia from AD patients and MS patients, and between genes downregulated in aging and MS 36 . Equally, within mouse models of aging and neurodegeneration, Spp1, Ccl2, Ccl3, and Ccl4 are frequently upregulated and associated with proinflammatory microglial states 2,37–40 . It seems likely that this gene signature may also be associated with a senescent state among subsets of microglia, as these genes are highly enriched in senescent cells, and senescent microglia have been found in mouse models of Alzheimer’s disease and traumatic brain injury where these genes are upregulated 14,15,22,24,41 .…”

“…While there is a consensus that microglia occupy a continuum of states and functions dependent on their intrinsic gene and protein expression, and cues from their local microenvironment, equally there is significant evidence for certain genes consistently dysregulated in microglia across numerous different diseases and in aging 6,10 . It is important to note that many studies on human microglia are often limited by the amount and quality of microglial nuclei, and systematic analysis of microglial gene expression changes compared to mouse gene expression changes in aging and disease finds that microglial signatures comparing across mice and human are not highly similar 2,36 . Still, when considering within humans, microglia demonstrate consistent gene expression changes between aging and neurodegenerative diseases, particularly demonstrating a shared expression profile between microglia from AD patients and MS patients, and between genes downregulated in aging and MS 36 .…”

“…Extravasation and activation of T-cells, B-cells, and macrophages in the central nervous system (CNS), alongside gliosis of resident astrocytes and microglia contribute to demyelination, axonal injury, and neuronal and oligodendrocyte cell death 1 . Transcriptional studies of CNS glial cells have identified numerous dysregulated pathways, including complement signaling, interferon signaling, and antigen presentation in astrocytes, microglia, and oligodendrocytes 2 .…”

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation

“…Recent studies suggest that astrocyte reactivity is an early marker linking Aβ with initial tau pathology, potentially serving as an indicator of early-stage AD and a criterion for clinical trial recruitment [ 41 ]. Through RNA-sequencing data analysis, novel genes related to inflammation have been identified in astrocytes, oligodendrocytes, and microglia in MS [ 42 ]. Furthermore, translatome data indicates that microglia and astrocytes have distinct roles in inflammation during the hyperacute and acute phases following stroke [ 43 ].…”

Cellular rejuvenation protects neurons from inflammation mediated cell death

“…It is certain that the complex inflamed, and injurious environment alters intrinsic neuronal gene programs, as it does to the CNS glial cells, and these altered gene programs may contribute to or protect from neurodegeneration in the disease 18 . Animal models of disease are useful for assaying neuronal changes in response to pathological inflammation, enabling sampling from various timepoints across a standardized disease course.…”