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An examination of the effects of the environment on transplanted human interneuron progenitors in temporal lobal epilepsy

Zhu, Ying 2018. An examination of the effects of the environment on transplanted human interneuron progenitors in temporal lobal epilepsy. PhD Thesis, Cardiff University.
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Abstract

Loss or dysfunction of GABAergic inhibitory neurons is involved in many neurological disorders, including epilepsy. Transplantation of GABAergic neuron progenitors in rodent models of epilepsy significantly reduces seizure occurrence and duration. Therefore, transplantation of GABAergic neuron progenitor of human origin is being considered as a potential therapy for drug resistant epilepsy. The microenvironment plays an important role in regulating survival, proliferation and differentiation of neuronal stem cells. Evidence shows an inflamed microenvironment with significant upregulation and secretion of inflammatory cytokines after seizures. Whilst the major emphasis to date has been on generating the optimal cell types for cell therapy in epilepsy, there has been little attention paid to the effects of the neuroinflammatory environment into which cells will be delivered. In this study, it is found that in a 3D model of human adult neural tissue excised at epilepsy surgery, the inflamed microenvironment reduced the survival, impaired neurite growth, and differentiation of in-vitro transplanted hESC-derived MGE progenitors. IL-1β was recognized as an important pro-inflammatory cytokine which affected the survival and differentiation of hESC-derived MGE progenitors in this model. Restored differentiation and promotion of neurite growth was observed in MGE progenitors by blocking the IL-1R. Further experiments in monolayer cultures on electrophysiology found MGE-like neurons were less excitable after acute exposure to IL-1β. The mechanism was due to reduction in sodium current rather than alternation in channel activation or inactivation kinetics. And this effect was not persistent when level of IL-1β returned to normal concentration. But when repetitively treated by IL-1β for a week, MGE-like neurons became unhealthy and their excitability reduced even more. In conclusion, the inflamed microenvironment, especially IL-1β is detrimental for survival, differentiation and electrophysiological activities of transplanted MGE-like neurons in this in-vitro primary human tissue model. The results suggest anti-inflammatory treatment could be beneficial to improve efficiency of neuron transplantation therapy. The results also potentially imply that neuroinflammation may cause a reduced excitability of interneurons as a potential mechanism for epilepsy.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Uncontrolled Keywords: MGE progenitor,GABAergic interneuron, neuron transplantation,Epilepsy,interleukin 1 beta, sodium current, neuron excitability
Date of First Compliant Deposit: 17 May 2019
Last Modified: 30 Jun 2019 02:05
URI: http://orca-mwe.cf.ac.uk/id/eprint/122400

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