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Reduced excitability and altered differentiation of transplanted hESC-derived MGE progenitors via IL-1β in inflamed epileptogenic human tissue
EANS Academy. Zhu Y. Sep 26, 2019; 276074; EP07047

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Abstract
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Background: Hippocampal interneuron loss/dysfunction is one of the earliest pathological changes in mesial temporal lobe epilepsy (mTLE). Transplantation of human embryonic stem cell-derived interneuron progenitors is a promising therapeutic strategy for mTLE. The major emphasis has been on generating the optimal cell types for cell therapy, but little attention has been paid to the effects of the neuro-inflammatory environment. We investigate the role of the pro-inflammatory cytokine IL-1β on transplanted interneuron progenitors in sclerotic human hippocampal 3D cultures (Hispots®)
Method: GFP labelled hESCs were cultured to generate Nkx2.1+ MGE progenitors. Nkx2.1+ GFP+ progenitors were co-cultured in hi-spots with cells dissociated from sclerotic or non-sclerotic hippocampal tissue collected from patients undergoing epilepsy surgery. The microenvironment was modulated by adding IL-RA or IL-1β into the culture medium. MGE progenitor survival, differentiation and neurite numbers/length were quantified using immunohistochemistry and Sholl analysis. Patch clamp was preformed to measure the effects of IL-1b on electrophysiological functionality of MGE-like neurons.
Results: Survival of MGE progenitors were significantly reduced in sclerotic hippocampal hi-spots compared with cortical hi-spots. MGE progenitors transplanted in hippocampal hi-spots exhibited shorter branch length (216.6 vs 400.1um) and lower proportion of Tuj1 (0.57 vs 0.76, P< 0.01) and GAD 67(0.27 vs 0.48) expressing cells. Treatment with IL-1R antagonist IL-1RA improved maximum neurite growth and proportion of Tuj1+ and GAD 67+ cells but didn't alter MGE progenitors' survival. MGE-like neurons grown in mono-layer cultures were less excitable after exposure to IL-1β. This was due to reduction in sodium currents (40%), especially when repetitively treated by IL-1β for a week, MGE-like neurons exhibited nearly 80% reduction of sodium current.
Conclusion: The inflamed microenvironment, especially IL-1β is detrimental for survival, differentiation and electrophysiological activities of MGE-like neurons in this in-vitro primary human tissue model. Anti-inflammatory treatment could improve survival and growth in neuronal transplantation therapy.
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