Role of Caveolin-1 in microglial phenotype: impact on Glioblastoma

Das Neves Neto, Catia 2021. Role of Caveolin-1 in microglial phenotype: impact on Glioblastoma. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Glioblastoma multiform (GBM) is a lethal brain tumour composed by many distinct cell types that are closely connected and dependent on their surrounding environment. Microglia are the brain immune cells, which are highly abundant in GBM and create an immunosuppressive microenvironment that promotes tumour progression. Caveolin-1 (Cav1) is the most important protein of caveolae and it is involved in cell signalling activity. In the GBM, Cav1 promotes the tumour invasion and it is correlated with a poor prognosis. In immunes cells, its role is not well explored, however it can be involved in immune response. Our hypothesis was that Cav1 could have an impact in the response of human microglia to the environment, influencing tumour progression. To test our hypothesis, a human microglia cell line and an iPSC cell line were used to generate Cav1 knockout clones using CRISPR-Cas9 technology. The iPSC was used to generated human microglia cells. Primary human microglia expressed low levels of Cav1, which could be regulated upon activation. The viral immortalized human microglia cells expressed strong Cav1 protein levels, possibly correlated with the immortalization procedure with SV40 large T antigen. This infection in combination with the culture conditions might lead to a constitutive pro-inflammatory phenotype, impacting the ability of microglia to react to other stimulus and to do phagocytosis. A slightly modified protocol to generate microglia from iPSC allowed the differentiated cells to be polarized towards pro-inflammatory and anti-inflammatory phenotype and to perform phagocytosis. In microglia, Cav1 was involved in the regulation of the inflammatory response, cell migration, phagocytosis, and sensitivity to temozolomide. The microglia cell line did not impact the tumour behaviour, likely due to the profile presented by the cells. However, the deletion of Cav1 in microglia derived from iPSC promoted the tumour invasion.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	18 May 2021
Last Modified:	18 May 2021 13:36
URI:	https://orca.cardiff.ac.uk/id/eprint/141415

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