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| Author(s): |
Thais Fernanda de Almeida Galatro
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2016-09-12 |
| Examining board members: |
Suely Kazue Nagahashi Marie;
Bartholomeus Johannes Leonardus Eggen;
Antonio Marcondes Lerário;
Marcos Vinicius Calfat Maldaun
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| Advisor: | Suely Kazue Nagahashi Marie |
| Abstract | |
Microglia are essential for central nervous system (CNS) homeostasis and innate neuroimmune function, and play important roles in neurodegeneration, brain aging and tumorigenesis. Diffuse gliomas are primary brain tumors characterized by infiltrative growth and high heterogeneity, which renders the disease mostly incurable. Advances in genetic analysis have characterized molecular alterations leading to impact on patients\' overall survival and clinical outcome, particularly in glioblastoma (GBM). However, glioma tumorigenicity is not controlled uniquely by its genetic alterations. The crosstalk between tumor cells, resident microglia and infiltrating monocytes/macrophages plays a crucial role in modulating glioma growth and aggressiveness. Here, we assess the activation status of microglia/macrophages in gliomas,including astrocytomas and oligodendrogliomas of different grades of malignancy, and present the gene expression profile of pure cortical human microglia and corresponding unsorted brain tissue. Using high-throughput DNA sequencing, we have classified GBM samples in Proneural, classical and mesenchymal. Next, we evaluated the activation status of microglia/macrophages within these samples. Despite the great heterogeneity, we observed higher levels of myeloid markers (IBA1, CD11b and CD68) in astrocytic tumors compared to oligodendrocytic ones and to non-neoplastic (NN) tissue. Anti-inflammation markers, such as CD163, are also more abundant in astrocytomas, as well as in the mesenchymal and classical GBM subtypes, while pro-inflammation markers, such as IL1-beta, show a more widespread expression throughout samples. Next, microglia were isolated from the parietal cortex of 25 autopsy samples of cognitively preserved humans and RNA sequenced. Overall, genes expressed by human microglia are similar to mouse microglia, such as CX3CR1, P2YR12, and ITGAM. Interestingly, a number of immune genes, not identified as mouse microglia signature genes, were abundantly expressed in human microglia, such as TLR, Fcy and SIGLEC receptors and NLRC5 and CIITA transcription factors. Comparison of microglia to monocyte and macrophage expression data underscored the CNS-specific functions of microglia and new markers were identified that distinguish human microglia from other myeloid cells. Our glioma-related data suggests an immune-suppressive and growth supportive characteristic for tumors with worse clinical outcome, linked to an activation profile of myeloid cells. This data is the first comprehensive pure human microglia gene expression profile; human microglia clearly differ from mouse microglia and other myeloid cells. These results will help further studies focusing on pure myeloid cells populations in glioma (AU) | |
| FAPESP's process: | 13/07704-3 - The role of microglia activation in human astrocytoma |
| Grantee: | Thais Fernanda de Almeida Galatro |
| Support Opportunities: | Scholarships in Brazil - Doctorate |