iPSC-derived reactive astrocytes from patients with multiple sclerosis protect cocultured neurons in inflammatory conditions

Abstract

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-β1 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.

Research progress of autoimmune diseases based on induced pluripotent stem cells

“…Hence, this may of modifying disease-susceptibility genes in iPSCs by gene-editing is still impractical. Thirdly, the heterogeneity of iPSCs derivatives remains poorly understood, although we know some factors that may reduce the therapeutic effect, such as donors and aging ( 46 , 178 ). For example, some studies showed that iPSCs-derived MSCs demonstrated a weaker therapeutic effect than MSCs from other sources ( 92 ).…”

“…Astrocytes are glial cells with several protective functions to the CNS, including neuron trophic support, synapse regulation, and BBB integrity ( 6 ). Although astrocytes have been successfully differentiated from iPSCs of MS patients ( 43 – 46 ), it is unclear whether MS-astrocytes and healthy controls-astrocytes are significantly different. Some studies have reported that astrocytes from MS and healthy control iPSCs lines had significant glutamate uptake capacity and similar transcriptome triggered by some pro-inflammatory cytokines ( 44 , 45 ).…”

“…reported that healthy control or autologous neurons cultured with iPSCs-derived reactive astrocytes from benign MS patients [an Expanded Disability Status Scale (EDSS) score <3 with full earning ability and a disease duration of over 15 years] exhibit less axonal damage than astrocytes from healthy controls and progressive MS patients [a rapid disability accumulation (EDSS > 6) within 15 years of disease duration] after treatment with TNF-α combined with IL-17A ( 44 ). This may be due to neurite-protective supernatants from benign MS cases containing a higher level of LIF, transforming growth factor (TGF)-β, and brain-derived neurotrophic factor (BDNF) that are classical neurotrophic factors induced by sustained activation of the JAK/STAT signaling ( 46 ). Although iPSCs-derived astrocytes help us understand the roles of astrocytes, their functional heterogeneity and complex subgroups which might be further identified by high-throughput sequencing techniques, limits our ability to apply astrocytes as a therapeutic target.…”

Stem cell therapies: a new era in the treatment of multiple sclerosis

“…Activation of the JAK/STAT pathway induced the production of soluble mediators such as LIF, BDNF, and TGF-β1, which exerted neuroprotective effects. Additionally, iPSC-induced astrocytes from BMS patients stabilized the TNF-α-induced NF-κB signaling pathway, thereby protecting cells from inflammatory neuronal damage ( 167 ).…”

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…Further iPSC-derived cerebral organoids from GWI veterans display cognitive deficits and impaired neurogenesis and could be used to establish GWI toxicants platform for developing personalized medicine approaches for the veterans [ 244 ]. Additionally, reactive astrocytes from Multiple Sclerosis patients were found to offer enhanced axonal protection under inflammatory conditions, indicating the therapeutic potential of modulating astrocyte phenotypes to reduce neuronal damage [ 245 ]. Further, the establishment of iPSC-derived BBB models has contributed to the understanding of BBB disorders, and to the study of the earliest stages of BBB dysfunction associated with the disease, which is difficult to ascertain from postmortem tissue [ 246 , 247 ].…”