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Deciphering the Role of Border-Associated Macrophages in Glioblastoma Development by Using Novel CD206-Transgenic Mouse Models


Petrova, Ekaterina. Deciphering the Role of Border-Associated Macrophages in Glioblastoma Development by Using Novel CD206-Transgenic Mouse Models. 2024, University of Zurich, Faculty of Science.

Abstract

Macrophages are the cells of immune system that take an active part in tissue homeostasis and immune defense. CD206, or mannose receptor (MR) is one of macrophage markers, expressed particularly high in brain border-associated macrophages and lung alveolar macrophages. In order to study the role of CD206+ macrophages, we generated the novel CD206 transgenic mouse models Mrc1Cre,EYFP and Mrc1CreER,EYFP, which allow specific targeting of CD206-expressing cells in both constitutive and inducible manner. Both strains exhibited CD206+ cell-specific EYFP expression, and by crossing them to the reporter (R26Ai14 and R26RFP) and depleting (R26DTA and Csf1r fl/fl) strains we managed to achieve highly efficient labelling and depletion of various macrophage subpopulations.

Glioblastoma is an aggressive primary brain cancer with short overall survival, characterized by a high number of tumour-associated macrophages (TAMs). Glioblastoma TAMs are a heterogeneous population, consisting of resident macrophages including microglia and border-associated macrophages (BAMs), and monocyte-derived macrophages (MdMs). General macrophage depletion strategies exploiting CSF1R blockade significantly improved outcome in mouse models of glioblastoma but failed in humans. Hence, a more detailed analysis of the contribution of each glioblastoma TAM subsets is needed since TAM subsets can have different roles and impact on the tumour growth. The role of BAMs in glioblastoma development is currently unknown. By using our novel Mrc1CreER,EYFP R26Ai14 and Mrc1CreER,EYFP R26DTA mouse strains, we showed that resident BAMs localized to the glioblastoma area and were in direct contact with both blood vessels and tumour cells. BAM depletion led to a significant increase in tumour size and increased immune cells infiltration, suggesting a recently unknown role of BAMs in glioblastoma pathogenesis.

Abstract

Macrophages are the cells of immune system that take an active part in tissue homeostasis and immune defense. CD206, or mannose receptor (MR) is one of macrophage markers, expressed particularly high in brain border-associated macrophages and lung alveolar macrophages. In order to study the role of CD206+ macrophages, we generated the novel CD206 transgenic mouse models Mrc1Cre,EYFP and Mrc1CreER,EYFP, which allow specific targeting of CD206-expressing cells in both constitutive and inducible manner. Both strains exhibited CD206+ cell-specific EYFP expression, and by crossing them to the reporter (R26Ai14 and R26RFP) and depleting (R26DTA and Csf1r fl/fl) strains we managed to achieve highly efficient labelling and depletion of various macrophage subpopulations.

Glioblastoma is an aggressive primary brain cancer with short overall survival, characterized by a high number of tumour-associated macrophages (TAMs). Glioblastoma TAMs are a heterogeneous population, consisting of resident macrophages including microglia and border-associated macrophages (BAMs), and monocyte-derived macrophages (MdMs). General macrophage depletion strategies exploiting CSF1R blockade significantly improved outcome in mouse models of glioblastoma but failed in humans. Hence, a more detailed analysis of the contribution of each glioblastoma TAM subsets is needed since TAM subsets can have different roles and impact on the tumour growth. The role of BAMs in glioblastoma development is currently unknown. By using our novel Mrc1CreER,EYFP R26Ai14 and Mrc1CreER,EYFP R26DTA mouse strains, we showed that resident BAMs localized to the glioblastoma area and were in direct contact with both blood vessels and tumour cells. BAM depletion led to a significant increase in tumour size and increased immune cells infiltration, suggesting a recently unknown role of BAMs in glioblastoma pathogenesis.

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Additional indexing

Item Type:Dissertation (monographical)
Referees:Greter Melanie, Becher Burkhard, Tugues Solsona Sonia, Ginhoux Florent
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Place of Publication:Zürich
Date:26 March 2024
Deposited On:26 Mar 2024 13:42
Last Modified:26 Mar 2024 13:42
Number of Pages:211
OA Status:Closed