Multiple sclerosis patient-derived CSF induces transcriptional changes in proliferating oligodendrocyte progenitors

Abstract

BACKGROUND Cerebrospinal fluid is in contact with brain parenchyma and ventricles, and its composition might influence the cellular physiology of oligodendrocyte progenitor cells (OPCs) thereby contributing to disease pathogenesis. OBJECTIVE To identify the transcriptional changes that distinguish the transcriptional response induced in proliferating rat OPCs upon exposure to CSF from PPMS or RRMS patients and other neurological controls. METHODS We performed gene microarray analysis of OPCs exposed to CSF from neurological controls, or definitive RRMS or PPMS disease course. Results were confirmed by qRT-PCR, immunocytochemistry and western blot of cultured cells and validated in human brain specimens. RESULTS We identified common and unique genes for each treatment group. Exposure to CSF from PPMS uniquely induced branching of cultured progenitors and related transcriptional changes, including up-regulation (p < 0.05) of the adhesion molecule GALECTIN-3/Lgals3, which was also detected at the protein level in brain specimens from PPMS patients. However it also resulted in discordant patterns of gene expression when compared with the transcriptional program of oligodendrocyte differentiation during development. CONCLUSIONS Despite evidence of morphological differentiation induced by exposure to CSF of PPMS patients, the overall transcriptional response elicited in cultured OPCs was consistent with the activation of an aberrant transcriptional program.

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis

“…24 According to these findings, we speculate that inflammation in the brain lesions of progressive MS cause upregulation of galectin-3 in glial cells, resulting in the generation of antibodies against galectin-3. These antibodies can then enter the blood circulation through antibodymediated BBB disruption from the CNS parenchyma.…”

BRCA1/BRCA2‐containing complex subunit 3 controls oligodendrocyte differentiation by dynamically regulating lysine 63‐linked ubiquitination

“…Based on the findings shown in Figure , K63Ub‐K63 deubiquitination might be involved in OL differentiation. A transcriptome analysis has revealed decreased levels of BRCC3, a known K63‐specific metalloprotease DUB, in OPCs treated with cerebrospinal fluid (CSF) collected from patients with MS (Haines et al, ). Moreover, BRCC3 is expressed at higher levels in cells of the OL lineage among other neural cell types, according to the RNA sequencing database (Zhang et al, ).…”

“…According to the findings from other researchers using an Agilent microarray analysis, BRCC3 is downregulated on cultured OPCs exposed to the CSF collected from patients with MS (Haines et al, ). In conjunction with our data showing decreased expression of BRCC3 at the lesion site of the brain sections prepared from MS patients, an unresolved question is whether the demyelinating micro‐environmental factor(s) inhibited BRCC3 expression in OPCs or in OLs.…”

“…Based on the findings shown in Figure 1, K63Ub-K63 deubiquitination might be involved in OL differentiation. A transcriptome analysis has revealed decreased levels of BRCC3, a known K63-specific metalloprotease DUB, in OPCs treated with cerebrospinal fluid (CSF) collected from patients with MS (Haines et al, 2015).…”

Bioenergetic Failure in Rat Oligodendrocyte Progenitor Cells Treated with Cerebrospinal Fluid Derived from Multiple Sclerosis Patients

“…Differential shaking, followed by magnetic beads immunoselection, was used to isolate progenitors (Haines et al, 2015). Briefly, cells were incubated with the A2B5 antibody, purified using magnetic beads (Miltenyi Biotec), and then plated at a density of 2 × 10 5 cells/ml on poly- D -lysine coated 10 cm plates.…”