Content area
Full text
Multiple sclerosis (MS) is the most common chronic central nervous system inflammatory disease. Individual courses are highly variable, with complete remission in some patients and relentless progression in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared with progressive MS (PMS). We differentiated neurons and astrocytes that were then stressed with inflammatory cytokines typically associated with MS phenotypes. TNF-α/IL-17A treatment increased neurite damage in MS neurons from both clinical phenotypes. In contrast, TNF-α/IL-17A-reactive BMS astrocytes cultured with healthy control neurons exhibited less axonal damage compared with PMS astrocytes. Accordingly, single-cell transcriptomic BMS astrocyte analysis of cocultured neurons revealed upregulated neuronal resilience pathways; these astrocytes showed differential growth factor expression. Furthermore, supernatants from BMS astrocyte/neuronal cocultures rescued TNF-α/IL-17-induced neurite damage. This process was associated with a unique LIF and TGF-ß1 growth factor expression, as induced by TNF-α/IL-17 and JAK-STAT activation. Our findings highlight a potential therapeutic role of modulation of astrocyte phenotypes, generating a neuroprotective milieu. Such effects could prevent permanent neuronal damage.
Introduction
The major multiple sclerosis (MS) research advances involve inflammatory mechanisms. With new knowledge, effective anti-lymphocyte treatments were developed. These therapies reduced or terminated MS relapses and MRI activity. However, life-threat-ening opportunistic infections and cancer also developed (1). Despite treatment, many MS patients progress to disability. The deterioration correlates with slowly expanding preexisting MRI lesions (2). Peripheral immune cells are commonly scarce, or even absent, in these sites, although ICAM-1 and MHC-II are strongly upregulated on adjacent glial cells. This state of affairs indicates ongoing active inflammation driven by central nervous system-endogenous cells (3). We strove to better understand the underlying endogenous central nervous system (CNS) inflammatory mechanisms. We hypothesized that the process involves neurodegeneration with simultaneous neuro-regeneration (4). Not only proinflammatory but also potentially neuroprotective and regenerative mechanisms could be inherent in the astrocytes of these MS patients. Such a state of affairs could explain the heterogeneous individual MS outcomes. In early MS, astrocytes are involved and have multiple potential roles in damage and repair (5). Furthermore, astrocytes have been described as a major component in other neurological diseases (6), which highlights their central role supporting a sound neuronal network activity and CNS integrity. We focused on two MS clinical phenotype extremes, benign...