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

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Item Type:Article
Title:iPSC-derived reactive astrocytes from patients with multiple-sclerosis protect cocultured neurons in inflammatory conditions
Creators Name:Kerkering, J. and Muinjonov, B. and Rosiewicz, K.S. and Diecke, S. and Biese, C. and Schiweck, J. and Chien, C. and Zocholl, D. and Conrad, T. and Paul, F. and Alisch, M. and Siffrin, V.
Abstract:Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS). The individual course is highly variable with complete remission in some patients and relentless courses in others. We generated induced pluripotent stem cells (iPSCs) to investigate possible mechanisms in benign MS (BMS), compared to progressive MS (PMS). We differentiated neurons and astrocytes that were then stressed with inflammatory cytokines typically associated with MS. TNFα/IL-17A treatment increased neurite damage in MS neurons irrespective of clinical phenotypes. In contrast, TNFα/IL-17A-reactive BMS astrocytes cultured with healthy control (HC) neurons exhibited significantly decreased axonal damage, compared to PMS astrocytes. Accordingly, single cell transcriptomic analysis of BMS-astrocyte co-cultured neurons demonstrated upregulated pathways of neuronal resilience, namely these astrocytes revealed differential growth factor expression. Moreover, supernatants from BMS astrocyte-neuron co-cultures rescued TNFα/IL-17-induced neurite damage. This process was associated with the unique expression of the growth factors, LIF and TGF-β1, as induced by TNFα/IL-17 and JAK-STAT activation. Our findings highlight a potential therapeutic role of modulating astrocyte phenotypes that generate a neuroprotective milieu preventing permanent neuronal damage.
Keywords:Multiple Sclerosis, Induced Pluripotent Stem Cells, Neurodegeneration, Inflammation
Source:Journal of Clinical Investigation
Publisher:American Society for Clinical Investigation
Page Range:e164637
Date:3 July 2023
Official Publication:https://doi.org/10.1172/JCI164637
PubMed:View item in PubMed

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